System and method for health monitoring using a non-invasive, multi-band biosensor

ABSTRACT

A biosensor includes a PPG circuit that emits light directed at skin tissue at a plurality of wavelengths. A first and second spectral response of light reflected from the tissue is obtained around a first wavelength and a second wavelength. Using absorption coefficients for substances at the plurality of wavelengths, concentration levels of a plurality of substances may then be determined from the spectral responses. The biosensor may thus be used to determine concentrations of a plurality of substances in arterial blood flow using the spectral response.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. §120 as acontinuation application to U.S. Utility application Ser. No. 15/275,388entitled, “SYSTEM AND METHOD FOR HEALTH MONITORING USING A NON-INVASIVE,MULTI-BAND BIOSENSOR,” filed Sep. 24, 2016, and hereby expresslyincorporated by reference herein.

U.S. Utility application Ser. No. 15/275,388 claims priority as acontinuation in part under 35 U.S.C. §120 to U.S. Utility applicationSer. No. 14/866,500 entitled, “System and Method for GlucoseMonitoring,” filed Sep. 25, 2015, and hereby expressly incorporated byreference herein.

U.S. Utility application Ser. No. 15/275,388 claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 62/194,264 entitled,“System and Method for Glucose Monitoring,” filed Jul. 19, 2015, andhereby expressly incorporated by reference herein.

U.S. Utility application Ser. No. 15/275,388 claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 62/276,934 entitled,“System and Method for Health Monitoring including a Remote Device,”filed Jan. 10, 2016, and hereby expressly incorporated by referenceherein.

U.S. Utility application Ser. No. 15/275,388 claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 62/307,375 entitled,“System and Method for Health Monitoring using a Non-Invasive,Multi-Band Sensor,” filed Mar. 11, 2016, and hereby expresslyincorporated by reference herein.

U.S. Utility application Ser. No. 15/275,388 claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 62/312,614 entitled,“System and Method for Determining Biosensor Data using a Broad SpectrumLight Source,” filed Mar. 24, 2016, and hereby expressly incorporated byreference herein.

U.S. Utility application Ser. No. 15/275,388 claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 62/373,283 entitled,“System and Method for a Biosensor Monitoring and Tracking Band,” filedAug. 10, 2016, and hereby expressly incorporated by reference herein.

U.S. Utility application Ser. No. 15/275,388 claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 62/383,313 entitled,“System and Method for a Drug Delivery and Biosensor Patch,” filed Sep.2, 2016, and hereby expressly incorporated by reference herein.

FIELD

This application relates to a systems and methods of non-invasive,autonomous health monitoring, and in particular a health monitoringsensor that monitors a patient's vitals and detects concentration levelsor indicators of substances in blood vessels.

BACKGROUND

A patient's vitals, such as temperature, blood oxygen levels, bloodpressure, etc., may need to be monitored periodically typically usingone or more instruments. For example, instruments for obtaining vitalsof a patient include blood pressure cuffs, thermometers, SaO₂measurement devices, glucose level meters, etc. Often, multipleinstruments must be brought to a patient's room by a caretaker, and themeasurements collected using the multiple instruments. This monitoringprocess can be time consuming, inconvenient and is not alwayscontinuous. It may also disrupt sleep of the patient. The measurementsof the vitals must then be manually recorded into the patient'selectronic medical record.

In addition, detection of substances and measurement of concentrationlevel or indicators of various substances in a patient's blood vesselsis important in health monitoring. Currently, detection of concentrationlevels of blood substances is performed by drawing blood from a bloodvessel using a needle and syringe. The blood sample is then transportedto a lab for analysis. This type of monitoring is invasive,non-continuous and time consuming.

One current non-invasive method is known for measuring the oxygensaturation of blood using pulse oximeters. Pulse oximeters detect oxygensaturation of hemoglobin by using, e.g., spectrophotometry to determinespectral absorbencies and determining concentration levels of oxygenbased on Beer-Lambert law principles. In addition, pulse oximetry mayuse photoplethysmography (PPG) methods for the assessment of oxygensaturation in pulsatile arterial blood flow. The subject's skin at a‘measurement location’ is illuminated with two distinct wavelengths oflight and the relative absorbance at each of the wavelengths isdetermined. For example, a wavelength in the visible red spectrum (forexample, at 660 nm) has an extinction coefficient of hemoglobin thatexceeds the extinction coefficient of oxihemoglobin. At a wavelength inthe near infrared spectrum (for example, at 940 nm), the extinctioncoefficient of oxihemoglobin exceeds the extinction coefficient ofhemoglobin. The pulse oximeter filters the absorbance of the pulsatilefraction of the blood, i.e. that due to arterial blood (AC components),from the constant absorbance by nonpulsatile venous or capillary bloodand other tissue pigments (DC components), to eliminate the effect oftissue absorbance to measure the oxygen saturation of arterial blood.Such PPG techniques are heretofore been limited to determining oxygensaturation.

As such, there is a need for a patient monitoring system that includes acontinuous and non-invasive biosensor that measures patient vitals andmonitors concentration levels or indicators of one or more substances inblood flow.

SUMMARY

According to a first aspect, a biosensor includes a PPG circuitconfigured to emit light having at least a first wavelength and a secondwavelength directed at skin tissue of a patient, generate a firstspectral response using light around the first wavelength reflected fromthe skin tissue of the patient and generate a second spectral responseusing light around the second wavelength reflected from the skin tissueof the patient. The biosensor further includes a processing circuitconfigured to isolate a systolic point and a diastolic point in thefirst spectral response and obtain a value L_(λ1) using a ratio of thesystolic point and the diastolic point in the first spectral responseand isolate a systolic point and a diastolic point in the secondspectral response and obtain a value L_(λ2) using a ratio of thesystolic point and diastolic point in the second spectral response. Thebiosensor obtains a value R_(λ1, λ2) from a ratio of the value L_(λ1)and the value L_(λ2), wherein the value R_(λ1, λ2) is an indicator ofone or more liver enzymes and obtains a blood alcohol level using acalibration table and the value R_(λ1, λ2). The biosensor may transmitthe blood alcohol level for display.

According to a second aspect, a biosensor includes a PPG circuitconfigured to generate at least a first spectral response for lightreflected around a first wavelength from skin tissue of the patient andgenerate at least a second spectral response for light reflected arounda second wavelength from the skin tissue of the patient. The biosensorincludes a processing circuit configured to obtain a value L_(λ1) usingthe first spectral response, wherein the value L_(λ1) isolates the firstspectral response due to pulsating arterial blood flow; obtain a valueL_(λ2) using the second spectral response, wherein the value L_(λ2)isolates the second spectral response due to pulsating arterial bloodflow; and obtain a value R_(λ1, λ2) from a ratio of the value L_(λ1) andthe value L_(λ2). The processing circuit is further configured to obtaina liver enzyme indicator based on the value R_(λ1, λ2) that indicates aliver enzyme concentration level in the pulsating arterial blood flowand obtain a blood alcohol level using a calibration table and the valueR_(λ1, λ2).

According to a third aspect, a method for measuring blood alcohol levelsincludes generating at least a first spectral response for lightreflected around a first wavelength from skin tissue of the patient andgenerating at least a second spectral response for light detected arounda second wavelength reflected from the skin tissue of the patient. Themethod further includes obtaining a value L_(λ1) using the firstspectral response, wherein the value L_(λ1) isolates the first spectralresponse due to pulsating arterial blood flow, obtaining a value L_(λ2)using the second spectral response, wherein the value L_(λ2) isolatesthe second spectral response due to pulsating arterial blood flow, andobtaining a value R_(λ1, λ2) from a ratio of the value L_(λ1) and thevalue R_(λ2), wherein the value R_(λ1, λ2) is the indicator of aconcentration level of a liver enzyme of the patient. The method furtherincludes obtaining a blood alcohol concentration level of the patientfrom a calibration table and the value R_(λ1, λ2), wherein thecalibration table includes a range of R_(λ1, λ2) values and correlatedblood alcohol concentration levels and transmitting the blood alcoholconcentration level of the patient for display.

According to a fourth aspect, a biosensor is configured for installationin machinery and includes a PPG circuit configured to generate at leasta first spectral response for light reflected around a first wavelengthfrom skin tissue of the patient and generate at least a second spectralresponse for light reflected around a second wavelength from the skintissue of the patient. A processing circuit is configured to obtain avalue L_(λ1) using the first spectral response, wherein the value L_(λ1)isolates the first spectral response due to pulsating arterial bloodflow, obtain a value L_(λ2) using the second spectral response, whereinthe value L_(λ2) isolates the second spectral response due to pulsatingarterial blood flow, and obtain a value R_(λ1, λ2) from a ratio of thevalue L_(λ1) and the value L_(λ2). The processing circuit is furtherconfigured to obtain a liver enzyme indicator based on the valueR_(λ1, λ2) that indicates a liver enzyme concentration level in thepulsating arterial blood flow, obtain a blood alcohol level using acalibration table and the value R_(λ1, λ2), and generate a transmissionto the machinery to control operation of the machinery in response tothe blood alcohol level. The processing circuit may further beconfigured to compare the blood alcohol level to a predeterminedthreshold, determine the blood alcohol level exceeds the predeterminedthreshold, and generate a transmission to an ignition system of thevehicle to prevent operation of the machinery.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a schematic block diagram of an exemplary embodimentof a biosensor.

FIG. 2 illustrates a schematic block diagram illustrating an embodimentof the PPG circuit in more detail.

FIG. 3 illustrates a schematic block diagram of another exemplaryembodiment of the the PPG circuit.

FIG. 4 illustrates a logical flow diagram of an embodiment of a methodfor determining concentration of one or more substances usingBeer-Lambert principles.

FIG. 5A and FIG. 5B illustrate schematic block diagrams of an embodimentof a method for photoplethysmography (PPG) techniques.

FIG. 6 illustrates a schematic diagram of a graph of actual clinicaldata obtained using PPG techniques at a plurality of wavelengths.

FIG. 7 illustrates a schematic block diagram of an embodiment ofoperation of the biosensor.

FIG. 8 illustrates a logical flow diagram of an embodiment of a methodof determining concentration levels of one or more substances.

FIG. 9 illustrates a logical flow diagram of another embodiment of amethod of determining concentration levels of one or more substances.

FIG. 10 illustrates a schematic block diagram of another embodiment of abiosensor using a broad spectrum light source.

FIG. 11A illustrates a graph of an embodiment of an output of a broadspectrum light source.

FIG. 11B illustrates a graph with an embodiment of an exemplary spectralresponse of detected light across a broad spectrum.

FIG. 12 illustrates a logical flow diagram of an exemplary method todetermine blood concentration levels of a plurality of substances usingthe spectral response for a plurality of wavelengths.

FIG. 13 illustrates a logical flow diagram of an exemplary method todetermine blood concentration levels of a single substance using thespectral response for a plurality of wavelengths.

FIG. 14 illustrates an exemplary graph of spectral responses of aplurality of wavelengths from clinical data using the biosensor.

FIG. 15 illustrates a logical flow diagram of an exemplary method todetermine an absorption coefficients μ of a substance at a wavelength λ.

FIG. 16 illustrates a logical flow diagram of an embodiment of a methodof determining concentration levels of one or more substances.

FIG. 17A illustrates an exemplary embodiment of a form factor of thebiosensor.

FIG. 17B illustrates an exemplary embodiment of another form factor ofthe biosensor.

FIG. 18A illustrates an exemplary embodiment of another form factor ofthe biosensor.

FIG. 18B illustrates an exemplary embodiment of another form factor ofthe biosensor.

FIG. 19A illustrates an exemplary embodiment of another form factor ofthe biosensor.

FIG. 19B illustrates an exemplary embodiment of another form factor ofthe biosensor.

FIG. 20 illustrates a schematic block diagram of an embodiment of anexemplary network in which the the biosensor described herein mayoperate.

FIG. 21A illustrates a schematic block diagram of an embodiment of anetwork illustrating interoperability of a plurality of bio sensors.

FIG. 21B illustrates a logical flow diagram of an embodiment of a methodfor adjusting operation of the biosensor in response to a position ofthe biosensor.

FIG. 22 illustrates a schematic drawing of an exemplary embodiment ofresults of clinical data obtained using the biosensor from a firstpatient.

FIG. 23 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from the firstpatient.

FIG. 24 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from a secondpatient.

FIG. 25 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from the secondpatient.

FIG. 26 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from a thirdpatient.

FIG. 27 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from a fourthpatient.

FIG. 28 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from a fifthpatient.

FIG. 29 illustrates a schematic drawing of another exemplary embodimentof results of clinical data obtained using the biosensor from the fifthpatient.

FIG. 30 illustrates a schematic drawing of an exemplary embodiment ofusing the biosensor for measurements of a liver enzyme.

FIG. 31 illustrates a schematic block diagram of an embodiment of amethod for determining concentration levels or indicators of substancesin pulsating blood flow in more detail.

FIG. 32 illustrates a schematic block diagram of an exemplary embodimentof a graph 3200 illustrating the extinction coefficients over a range offrequencies for a plurality of hemoglobin compounds.

DETAILED DESCRIPTION

The word “exemplary” or “embodiment” is used herein to mean “serving asan example, instance, or illustration.” Any implementation or aspectdescribed herein as “exemplary” or as an “embodiment” is not necessarilyto be construed as preferred or advantageous over other aspects of thedisclosure. Likewise, the term “aspects” does not require that allaspects of the disclosure include the discussed feature, advantage, ormode of operation.

Embodiments will now be described in detail with reference to theaccompanying drawings. In the following description, numerous specificdetails are set forth in order to provide a thorough understanding ofthe aspects described herein. It will be apparent, however, to oneskilled in the art, that these and other aspects may be practicedwithout some or all of these specific details. In addition, well knownsteps in a method of a process may be omitted from flow diagramspresented herein in order not to obscure the aspects of the disclosure.Similarly, well known components in a device may be omitted from figuresand descriptions thereof presented herein in order not to obscure theaspects of the disclosure.

Overview

A non-invasive and continuous biosensor is implemented in a compact formfactor, such as on a finger, patch, wrist band or ear piece. Due to itscompact form factor, the biosensor may be configured for measurements onvarious skin surfaces of a patient, including on a forehead, arm, wrist,abdominal area, chest, leg, ear lobe, finger, toe, ear canal, etc. Thebiosensor includes one or more sensors for detecting biosensor data,such as a patient's vitals, activity levels, or concentrations ofsubstances in the blood flow of the patient. For example, the biosensormay include a temperature sensor having an array of sensors positionedadjacent to the skin of the patient. The biosensor may also include anactivity monitor to determine activity level and/or positioning of thepatient. The biosensor may also include a photoplethysmograpy (PPG)sensor. The PPG sensor may be configured to detect oxygen saturation(SPO₂) levels in blood flow, as well as heart rate and blood pressure.

In addition, the PPG sensor is configured to monitor concentrationlevels or indicators of one or more substances in the blood flow of thepatient. In one aspect, the PPG sensor may non-invasively andcontinuously detect diabetic parameters, such as base insulinresistance, insulin response in response to caloric intake, nitric oxide(NO) n levels, glucose levels, and predict diabetic risk or diabeticprecursors, in pulsatile arterial blood flow. In another aspect, the PPGsensor may measure vascular health using NO levels. In another aspect,the PPG sensor may detect blood alcohol levels in pulsatile arterialblood flow. In another aspect, the PPG sensor may detect cytochrome P450proteins or one or more other liver enzymes or proteins. In anotheraspect, the PPG sensor may detect digestive parameters, such asdigestion phase 1 and 2 responses, and caloric intake. The PPG sensormay detect various electrolyte concentration levels or blood analytelevels, such as bilirubin and sodium and potassium. For example, the PPGsensor may detect sodium NACL concentration levels in the arterial bloodflow to determine dehydration. In yet another aspect, the PPG sensor maybe configured to help diagnose cancer by detecting proteins or abnormalcells or other elements or compounds associated with cancer. In anotheraspect, the PPG sensor may detect white blood cell counts.

Embodiment—Biosensor Components

FIG. 1 illustrates a schematic block diagram of an exemplary embodimentof a biosensor 100. The biosensor 100 includes one or more processingcircuits 102 communicatively coupled to a memory device 104. In oneaspect, the memory device 104 may include one or more non-transitoryprocessor readable memories that store instructions which when executedby the processing circuit 102, causes the processing circuit 102 toperform one or more functions described herein. The memory device 104may also include an EEPROM to store a patient identification (ID) 172that is associated with a patient being monitored by the biosensor 100.The memory device 104 may also store an electronic medical record (EMR)or portion of the EMR associated with the patient being monitored by thebiosensor 100. The biosensor data obtained by the biosensor 100 may bestored in the EMR as well as the patient medical history. The processingcircuit 102 may be co-located with one or more of the other circuits inthe biosensor 100 in a same physical encasement or located separately ina different physical encasement or located remotely. In an embodiment,the biosensor 100 is battery operated and includes a battery 108, suchas a lithium ion battery. The biosensor 100 may also include a displayconfigured to display the biosensor data.

The biosensor 100 further includes a transceiver 106. The transceiver106 may include a wireless or wired transceiver configured tocommunicate with one or more devices over a LAN, MAN and/or WAN. In oneaspect, the wireless transceiver may include a Bluetooth enabled (BLE)transceiver or IEEE 802.11ah, Zigbee, IEEE 802.15-11 or WLAN (such as anIEEE 802.11 standard protocol) compliant transceiver. In another aspect,the wireless transceiver may operate using RFID, short range radiofrequency, infrared link, or other short range wireless communicationprotocol. In another aspect, the wireless transceiver may also includeor alternatively include an interface for communicating over a cellularnetwork. In an embodiment, the wireless transceiver may include a thinfoil for an antenna that is specially cut and includes a carbon padcontact to a main PCB of the biosensor 100. This type of antenna isinexpensive to manufacture and may be printed on the inside of anenclosure for the biosensor 100 situated away from the skin of thepatient to minimize absorption. The transceiver 106 may also include awired transceiver interface, e.g., a USB port or other type of wiredconnection, for communication with one or more other devices over a LAN,MAN and/or WAN.

The biosensor 100 includes one or more types of sensors, such as a PPGcircuit 110, a temperature sensor 112 or an activity monitoring circuit114. The temperature sensor 112 is configured to detect a temperature ofa patient. For example, the temperature sensor 112 may include an arrayof sensors (e.g., 16×16 pixels) positioned on a side of the biosensor100 such that the array of sensors are adjacent to the skin of thepatient. The array of sensors then detects an indication of thetemperature of the patient from the skin.

The activity monitoring circuit 114 is configured to monitor theactivity level of the patient. For example, the activity monitoringcircuit 114 may include a multiple axes accelerometer that measures aposition of the patient and motion of the patient. In one aspect, theactivity monitoring circuit 114 determines periods of activity and rest.For example, the activity monitoring circuit 114 monitors and recordsperiods of rest that meet a predetermined threshold of low motion oractivity level, such as sitting, lying, sleeping, etc. The activitymonitoring circuit 114 may also monitor and record periods of activitythat meet a predetermined threshold of motion or activity level, such aswalking, running, lifting, squatting, etc. The biosensor 100 is thenconfigured to measure and store the patient vitals with an indicator ofthe activity level of the patient. For example, blood oxygen levels mayvary greatly in patients with COPD during rest and activity. The vitalsof the patient are tracked during periods of activity and rest and thelevel of activity at time of measuring the vitals is recorded. Thebiosensor 100 is thus configured to associate measurements of patientvitals with the activity level of the patient.

In another aspect, to help lower power consumption, in an embodiment,the biosensor 100 includes a rest mode. For example, the activitymonitoring circuit 114 may signal a rest mode when a patient is asleepor meets a predetermined threshold of low activity level for apredetermined time period. In the rest mode, the biosensor 100 signalsone or more modules to halt non-essential processing functions. When theactivity monitoring circuit 114 detects a higher activity levelexceeding another predetermined threshold for a predetermined timeperiod, the the biosensor 100 signals one or more modules to exit restmode and resume normal functions. This activity monitoring feature helpsto save power and extend battery life of the biosensor 100.

In another aspect, the activity monitoring circuit is configured toinclude a fitness tracker application. The activity monitoring circuit114 may monitor a number of steps of the patient, amount and length ofperiods of sleep, amount and length of periods of rest, amount andlength of periods of activity, etc.

The biosensor 100 may also include an integrated drug delivery system116 or be communicatively coupled to a drug delivery system 116. Thebiosensor 100 may be configured to control delivery of medicine to apatient based on biosensor data obtained by the biosensor 100 asdescribed in more detail in U.S. Provisional Application No. 62/383,313entitled, “System and Method for a Drug Delivery and Biosensor Patch,”filed Sep. 2, 2016, which is expressly incorporated by reference herein.

The biosensor 100 may include a display 118. The biosensor 100 isconfigured to display a graphical user interface (GUI) that includesbiosensor data.

The biosensor 100 also includes a PPG circuit 110. The PPG circuit 110may be configured to detect oxygen saturation (SaO₂ or SpO₂) levels inblood flow, as well as heart rate and blood pressure. In addition, thePPG circuit 110 is configured to detect concentration levels orindicators of one or more substances in the blood flow of the patient asdescribed in more detail herein.

Embodiment—PPG Sensor

FIG. 2 illustrates a schematic block diagram illustrating an embodimentof the PPG circuit 110 in more detail. The PPG circuit 110 implementsphotoplethysmography (PPG) techniques for obtaining concentration levelsor indicators of one or more substances in pulsating arterial bloodflow. The PPG circuit 110 includes a light source 120 having a pluralityof light sources, such as LEDs 122 a-n, configured to emit light throughat least one aperture 128 a. The PPG circuit 110 is configured to directthe emitted light at an outer or epidermal layer of skin tissue of apatient. The plurality of light sources are configured to emit light inone or more spectrums, including infrared (IR) light, ultraviolet (UV)light, near IR light or visible light, in response to driver circuit118. For example, the biosensor 100 may include a first LED 122 a thatemits visible light and a second LED 122 b that emits infrared light anda third LED 122 c that emits UV light, etc. In another embodiment, oneor more of the light sources 122 a-n may include tunable LEDs or lasersoperable to emit light over one or more frequencies or ranges offrequencies or spectrums in response to driver circuit 118.

In an embodiment, the driver circuit 118 is configured to control theone or more LEDs 122 a-n to generate light at one or more frequenciesfor predetermined periods of time. The driver circuit 118 may controlthe LEDs 122 a-n to operate concurrently or progressively. The drivercircuit 118 is configured to control a power level, emission period andfrequency of emission of the LEDs 122 a-n. The biosensor 100 is thusconfigured to emit one or more frequencies of light in one or morespectrums that is directed at the surface or epidermal layer of the skintissue of a patient.

The PPG circuit 110 further includes one or more photodetector circuits130 a-n. For example, a first photodetector circuit 130 may beconfigured to detect visible light and the second photodetector circuit130 may be configured to detect IR light. The first photodetectorcircuit 130 and the second photodetector circuit 130 may also include afirst filter 160 and a second filter 162 configured to filter ambientlight and/or scattered light. For example, in some embodiments, onlylight received at an approximately perpendicular angle to the skinsurface of the patient is desired to pass through the filters. The firstphotodetector circuit 130 and the second photodetector circuit 132 arecoupled to a first A/D circuit 138 and a second A/D circuit 140.Alternatively, a single A/D circuit may be coupled to each of thephotodetector circuits 130 a-n.

In another embodiment, a single photodetector circuit 130 may beimplemented operable to detect light over multiple spectrums orfrequency ranges. For example, the photodetector circuit 130 may includea Digital UV Index/IR/Visible Light Sensor such as Part No. Si1145 fromSilicon Labs™.

The one or more photodetector circuits 130 include a spectrometer orother type of circuit configured to detect an intensity of light as afunction of wavelength or frequency to obtain a spectral response. Theone or more photodetector circuits 130 detects the intensity of lighteither transmitted through or reflected from tissue of a patient thatenters one or more apertures 128 b-n of the biosensor 100. For example,the light may be detected from transmissive absorption (e.g., through afingertip or ear lobe) or from reflection (e.g., reflected from aforehead or stomach tissue). The photodetector circuits 130 then obtaina spectral response of the detected light by measuring the intensity oflight either transmitted or reflected to the photodiodes.

FIG. 3 illustrates a schematic block diagram of another exemplaryembodiment of the the PPG circuit 110. In this embodiment, the biosensor100 is configured for emitting and detecting light through one or moreoptical fibers 152 a-c. The PPG circuit 110 is optically coupled to aplurality of optical fibers 152 a-c. In an embodiment, the plurality ofoptical fibers 152 includes a first optical fiber 152 a opticallycoupled to the light source 120. An optical coupler (not shown) tospread the angle of light emitted from the optical fiber 152 a may alsobe implemented. The optical fiber 152 a may have a narrow viewing anglesuch that an insufficient area of skin surface is exposed to the light.An optical coupler may be used to widen the viewing angle to increasethe area of skin surface exposed to the light.

A second optical fiber 152 b is optically coupled to a firstphotodetector circuit 130 and a third optical fiber 152 c is opticallycoupled to the second photodetector circuit 132. Other configurationsand numbers of the plurality of optical fibers 152 may also beimplemented.

In one aspect, the plurality of optical fibers 152 is situated within anouter ear canal to transmit and detect light in the ear canal. A lightcollimator 116, such as a prism, may be used to align a direction of thelight emitted from the light source 120. One or more filters 160 mayoptionally be implemented to receive the reflected light 142 from theplurality of optical fibers 152 b, 152 c. However, the filters 160 maynot be needed as the plurality of optical fibers 152 b, 152 c may besufficient to filter ambient light and/or scattered light.

Embodiment—PPG Measurement of Arterial Blood Flow

One or more of the embodiments of the biosensor 100 described herein isconfigured to detect a concentration level or indicator of one or moresubstances within blood flow, such as analyte levels, nitric oxidelevels, insulin resistance or insulin response after caloric intake andpredict diabetic risk or diabetic precursors. The biosensor 100 maydetect insulin response, vascular health, cardiovascular sensor,cytochrome P450 proteins (e.g. one or more liver enzymes or reactions),digestion phase 1 and 2 or caloric intake. The biosensor 100 may even beconfigured to detect proteins or other elements or compounds associatedwith cancer. The biosensor 100 may also detect various electrolytes andmany common blood analytic levels, such as bilirubin amount and sodiumand potassium. For example, the biosensor 100 may detect sodium NACLconcentration levels in the arterial blood flow to determinedehydration. The biosensor 100 may also detect blood alcohol levels invivo in the arterial blood flow. The biosensor 100 may also detect bloodpressure, peripheral oxygen (SpO₂ or SaO₂) saturation, heart rate,respiration rate or other patient vitals. Because blood flow to the skincan be modulated by multiple other physiological systems, the PPG sensor110 may also be used to monitor breathing, hypovolemia, and othercirculatory conditions.

In use, the biosensor 100 performs PPG techniques using the PPG circuit110 to detect the concentration levels of substances in blood flow. Inone aspect, the biosensor 100 analyzes reflected visible or IR light toobtain a spectrum response such as, the resonance absorption peaks ofthe reflected visible, UV or IR light. The spectrum response includesspectral lines that illustrate an intensity or power or energy at afrequency or wavelength in a spectral region of the detected light.

The ratio of the resonance absorption peaks from two differentfrequencies can be calculated and based on the Beer-Lambert law used toobtain various levels of substances in the blood flow. First, thespectral response of a substance or substances in the arterial bloodflow is determined in a controlled environment, so that an absorptioncoefficient α_(g1) can be obtained at a first light wavelength λ1 and ata second wavelength λ2. According to the Beer-Lambert law, lightintensity will decrease logarithmically with path length l (such asthrough an artery of length l). Assuming then an initial intensityI_(in) of light is passed through a path length l, a concentration C_(g)of a substance may be determined using the following equations:

At the first wavelength λ₁ , I _(in1)*10^(−(α) ^(g1) ^(C) ^(gw) ^(+α)^(w1) ^(C) ^(w) ^()*l)

At the second wavelength λ₂ , I ₂ =I _(in2)*10^(−(α) ^(g2) ^(C) ^(gw)^(+α) ^(w2) ^(C) ^(w) ^()*l)

wherein:

I_(in1) is the intensity of the initial light at λ₁

I_(in2) is the intensity of the initial light at λ₂

α_(g1) is the absorption coefficient of the substance in arterial bloodat λ₁

α_(g2) is the absorption coefficient of the substance in arterial bloodat λ₂

α_(w1) is the absorption coefficient of arterial blood at λ₁

α_(w2) is the absorption coefficient of arterial blood at λ₂

C_(gw) is the concentration of the substance and arterial blood

C_(w) is the concentration of arterial blood

Then letting R equal:

$R = \frac{\log \; 10\left( \frac{I\; 1}{{Iin}\; 1} \right)}{\log \; 10\left( \frac{I\; 2}{{Iin}\; 2} \right)}$

The concentration of the substance Cg may then be equal to:

${Cg} = {\frac{Cgw}{{Cgw} + {Cw}} = \frac{{\alpha_{w\; 2}R} - \alpha_{w\; 1}}{{\left( {\alpha_{w\; 2} - \alpha_{{gw}\; 2}} \right)*R} - \left( {\alpha_{w\; 1} - \alpha_{{gw}\; 1}} \right)}}$

The biosensor 100 may thus determine the concentration of varioussubstances in arterial blood using spectroscopy at two differentwavelengths using Beer-Lambert principles.

FIG. 4 illustrates a logical flow diagram of an embodiment of a method400 for determining concentration of one or more substances usingBeer-Lambert principles. The biosensor 100 transmits light at least at afirst predetermined wavelength in step 402 and at a second predeterminedwavelength in step 404. The biosensor 100 detects the light (reflectedfrom the skin or transmitted through the skin) and analyzes the spectralresponse at the first and second wavelengths to detect an indicator orconcentration level of one or more substances in the arterial blood flowat 406. In general, the first predetermined wavelength is selected thathas a high absorption coefficient for the targeted substance while thesecond predetermined wavelength is selected that has a low absorptioncoefficient for the targeted substance. Thus, it is generally desiredthat the spectral response for the first predetermined wavelength have ahigher intensity level than the spectral response for the secondpredetermined wavelength.

In another aspect, the biosensor 100 may transmit light at the firstpredetermined wavelength at 402 and in a range of approximately 1 nm to50 nm around the first predetermined wavelength. Similarly at 404, thebiosensor 100 may transmit light at the second predetermined wavelengthand in a range of approximately 1 nm to 50 nm around the secondpredetermined wavelength. The range of wavelengths is determined basedon the spectral response since a spectral response may extend over arange of frequencies, not a single frequency (i.e., it has a nonzerolinewidth). The light that is reflected or transmitted light by thetarget substance may by spread over a range of wavelengths rather thanjust the single predetermined wavelength. In addition, the center of thespectral response may be shifted from its nominal central wavelength orthe predetermined wavelength. The range of 1 nm to 50 nm is based on thebandwidth of the spectral response line and should include wavelengthswith increased light intensity detected for the targeted substancearound the predetermined wavelength.

The first spectral response of the light over the first range ofwavelengths including the first predetermined wavelength and the secondspectral response of the light over the second range of wavelengthsincluding the second predetermined wavelengths is then generated. Thebiosensor 100 analyzes the first and second spectral responses to detectan indicator or concentration level of one or more substances in thearterial blood flow at 406.

FIG. 5A and FIG. 5B illustrate schematic block diagrams of an embodimentof a method for photoplethysmography (PPG) techniques.Photoplethysmography (PPG) is used to measure time-dependent volumetricproperties of blood in blood vessels due to the cardiac cycle. Forexample, the heartbeat affects volume of arterial blood flow and theconcentration of absorption levels being measured in the arterial bloodflow. As shown in FIG. 5A, over a cardiac cycle 502, pulsating arterialblood 504 changes the volume of blood flow in an artery.

Incident light I_(O) 512 is directed at a tissue site and a certainamount of light is reflected or transmitted 518 and a certain amount oflight is absorbed 520. At a peak of arterial blood flow or arterialvolume, the reflected/transmitted light I_(L) 514 is at a minimum due toabsorption by the venous blood 508, nonpulsating arterial blood 506,pulsating arterial blood 504, other tissue 510, etc. At a minimum ofarterial blood flow or arterial volume during the cardiac cycle, thetransmitted/reflected light I_(H) 516 is at a maximum due to lack ofabsorption from the pulsating arterial blood 504.

The biosensor 100 is configured to filter the reflected/transmittedlight I_(L) 514 of the pulsating arterial blood 504 from thetransmitted/reflected light I_(H) 516. This filtering isolates the lightdue to reflection/transmission of substances in the pulsating arterialblood 504 from the light due to reflection/transmission from venous (orcapillary) blood 508, other tissues 510, etc. The biosensor 100 may thenmeasure the concentration levels of one or more substances from thereflected/transmitted light I_(L) 514 in the pulsating arterial blood504.

For example, as shown in FIG. 5B, incident light I_(O) 512 is directedat a tissue site by an LED 122 at one or more wavelengths. Thereflected/transmitted light I 518 is detected by photodetector 130. At apeak of arterial blood flow or arterial volume, the reflected lightI_(L) 514 is at a minimum due to absorption by venous blood 508,non-pulsating arterial blood 506, pulsating arterial blood 504, othertissue 510, etc. At a minimum of arterial blood flow or arterial volumeduring the cardiac cycle, the Incident or reflected light I_(H) 516 isat a maximum due to lack of absorption from the pulsating arterial blood504. Since the light I 518 is reflected or traverses through a differentvolume of blood at the two measurement times, the measurement providedby a PPG sensor is said to be a ‘volumetric measurement’ descriptive ofthe differential volumes of blood present at a certain location withinthe patient's arteriolar bed at different times. Though the above hasbeen described with respect to arterial blood flow, the same principlesdescribed herein may be applied to venous blood flow.

In general, the relative magnitudes of the AC and DC contributions tothe reflected/transmitted light signal I 518 may be used tosubstantially determine the differences between the diastolic time andthe systolic points. In this case, the difference between the reflectedlight I_(L) 514 and reflected light I_(H) 516 corresponds to the ACcontribution of the reflected light 518 (e.g. due to the pulsatingarterial blood flow). A difference function may thus be computed todetermine the relative magnitudes of the AC and DC components of thereflected light I 518 to determine the magnitude of the reflected lightI_(L) 514 due to the pulsating arterial blood 504. The describedtechniques herein for determining the relative magnitudes of the AC andDC contributions is not intended as limiting. It will be appreciatedthat other methods may be employed to isolate or otherwise determine therelative magnitude of the light I_(L) 514 due to pulsating arterialblood flow.

FIG. 6 illustrates a schematic diagram of a graph of actual clinicaldata obtained using PPG techniques at a plurality of wavelengths. Thebiosensor 100 emits light having a plurality of wavelengths during ameasurement period. The light at each wavelength (or range ofwavelengths) may be transmitted concurrently or sequentially. Theintensity of the reflected light at each of the wavelengths (or range ofwavelengths) is detected and the spectral response is measured over themeasurement period. The spectral response 606 for the plurality ofwavelengths obtained using the biosensor in clinical trials is shown inFIG. 6. In this clinical trial, two biosensors 100 attached to twoseparate fingertips of a patient were used to obtain the spectralresponses 606. The first biosensor 100 obtained the spectral responsefor a wavelength at 940 nm 610, a wavelength at 660 nm 612 and awavelength at 390 nm 614. The second biosensor 100 obtained the spectralresponse for a wavelength at 940 nm 616, a wavelength at 592 nm 618 anda wavelength at 468 nm 620.

In one aspect, the spectral response of each wavelength may be alignedbased on the systolic 602 and diastolic 604 points in their spectralresponses. This alignment is useful to associate each spectral responsewith a particular stage or phase of the pulse-induced local pressurewave within the blood vessel (which may mimic the cardiac cycle 606 andthus include systolic and diastolic stages and sub-stages thereof). Thistemporal alignment helps to determine the absorption measurementsacquired near a systolic point in time of the cardiac cycle and near thediastolic point in time of the cardiac cycle 606 associated with thelocal pressure wave within the patient's blood vessels. This measuredlocal pulse timing information may be useful for properly interpretingthe absorption measurements in order to determine the relativecontributions of the AC and DC components measured by the biosensor 110.So for one or more wavelengths, the systolic points 602 and diastolicpoints 604 in the spectral response are determined. These systolicpoints 602 and diastolic points 604 for the one or more wavelengths maythen be aligned as a method to discern concurrent responses across theone or more wavelengths.

In another embodiment, the the systolic points 602 and diastolic points604 in the absorbance measurements are temporally correlated to thepulse-driven pressure wave within the arterial blood vessels—which maydiffer from the cardiac cycle. In another embodiment, the biosensor 100may concurrently measure the intensity reflected at each the pluralityof wavelengths. Since the measurements are concurrent, no alignment ofthe spectral responses of the plurality of wavelengths may be necessary.FIG. 6 illustrates the spectral response of the plurality of wavelengthswith the systolic points 602 and diastolic points 604 aligned.

FIG. 7 illustrates a logical flow diagram of an embodiment of a method700 of the biosensor 100. In one aspect, the biosensor 100 emits anddetects light at a plurality of predetermined frequencies orwavelengths, such as approximately 940 nm, 660 nm, 390 nm, 592 nm, and468 nm. The light is pulsed for a predetermined period of time (such as100 usec or 200 Hz) sequentially at each predetermined wavelength. Inanother aspect, light may be pulsed in a wavelength range of 1 nm to 50nm around each of the predetermined wavelengths. Then, the spectralresponses are obtained for the plurality of wavelengths at 702. Thespectral response may be measured over a predetermined period (such as300 usec.). This measurement process is repeated sequentially pulsingthe light and obtaining spectral measurements over a desired measurementperiod, e.g. from 1-2 seconds to 1-2 minutes or 2-3 hours orcontinuously over days or weeks. Because the human pulse is typically onthe order of magnitude of one 1 HZ, typically the time differencesbetween the systolic and diastolic points are on the order of magnitudeof milliseconds or tens of milliseconds or hundreds of milliseconds.Thus, spectral response measurements may be obtained at a frequency ofaround 10-100 Hz over the desired measurement period.

A low pass filter (such as a 5 Hz low pass filter) is applied to thespectral response signal at 704. The relative contributions of the ACand DC components are obtained I_(AC+DC) and I_(AC). A peak detectionalgorithm is applied to determine the systolic and diastolic points at706. Beer Lambert equations are applied as described below at 708. Forexample, the L_(λ) values are then calculated for one or more of thewavelengths λ, wherein the L_(λ) values for a wavelength equals:

$L_{\lambda} = {{Log}\; 10\left( \frac{{IAC} + {D\; C}}{IDC} \right)}$

wherein I_(AC+DC) is the intensity of the detected light with AC and DCcomponents and I_(DC) is the intensity of the detected light with the ACfiltered by the low pass filter. The value L_(λ) isolates the spectralresponse due to pulsating arterial blood flow, e.g. the AC component ofthe spectral response.

A ratio R of the L_(λ) values at two wavelengths may then be determined.For example,

${{Ratio}\mspace{14mu} R} = \frac{L\; \lambda \; 1}{L\; \lambda \; 2}$

The L_(λ) values and Ratio R may be determined for one or more of thepredetermined measurement periods over a desired time period, e.g. from1-2 seconds to 1-2 minutes or 2-3 hours or continuously over days orweeks to monitor the values.

Embodiment—Determination of Indicators or Concentration Levels of One orMore Substances

In one aspect, based on unexpected results from clinical trials, it wasdetermined that a ratio R_(390,940) obtained at approximately L_(λ1)=390nm and L_(λ2)=940 is useful as a predictor or indicator of diabetic riskor diabetes. For example, during experimental clinical trials, spectralresponses were obtained during predetermined measurement periods over a1-2 minute time period at 390 nm and 940 nm. An R_(390,940) value wasobtained based on the spectral responses measured during a plurality ofthe predetermined measurement periods over the 1-2 minute time period.From the unexpected results of the clinical trials, an average or meanR_(390,940) value of less than 1 (e.g., approximately 0.5) indicatedthat a person has diabetes or early onset of diabetes. An average ormean R_(390,940) value of 2 or above indicated that a person has a lowerrisk of a diabetes diagnosis. An average or mean R_(390,940) value inthe 5-6 range indicated no current risk of diabetes. The R_(390,940)value determined using L_(λ1)=390 nm and L_(λ2)=940 was thus anindicator of diabetic risk and diabetes. Thus, based on the clinicaltrials, a non-invasive, quick 1-2 minute test produced an indicator ofdiabetes or diabetic risk in a person.

The R_(390,940) value with L_(λ1=390nm) and L_(λ2=940) may benon-invasively and quickly and easily obtained using the biosensor 100in a physician's office or other clinical setting or at home. In oneaspect, the R_(390,940) value may be used to determine whether furthertesting for diabetes needs to be performed. For example, upon detectionof a low R_(390,940) value, a clinician may then determine to performfurther testing and monitoring, e.g. using glucose ingestion tests overa longer period of time or using the biosensor 100 over a longer periodof time or other type of testing.

In particular, in unexpected results, it is believed that nitric oxideNO levels in the arterial blood flow is being measured at least in partby the biosensor 100 at λ1=390 nm. Since NO is partly in a gaseous formin blood vessels (prior to adhesion to hemoglobin), the total NOconcentration levels of in vitro blood samples, e.g. from a fingerprick, are not detected as the gas dissipates. Thus, the biosensor 100measurements to determine the L_(390nm) values are the first time NOconcentration levels in arterial blood flow have been measured directlyin vivo. In clinical trials performed as described further herein, inunexpected results, it seems that the NO levels are an indication ofinsulin response in the blood as well as concentration levels of insulinand/or glucose levels in the blood. The L_(λ1=390nm) and R valueobtained from L_(λ1=390nm) are thus an indicator of blood glucoselevels, insulin response and diabetic risk as well as vascular health.These unexpected results have advantages in early detection of diabeticrisk and easier, non-invasive monitoring of insulin resistance andglucose levels as well as vascular health and other conditions. Theseresults are discussed in more detail herein with illustrativeexperimental data.

The biosensor 100 may also function as a pulse oximeter using similarprinciples under Beer-lambert law to determine pulse and oxygensaturation levels in pulsating arterial flow. For example, a firstwavelength at approximately 940 nm and a second wavelength atapproximately 660 nm may be used to determine oxygen saturation levels.

The biosensor 100 may also be used to determine alcohol levels in theblood using wavelengths at approximately 390 nm and/or 468 nm. Inanother embodiment, an R_(468,940) value for at leastL_(468nm)/L_(940nm) may be used as a liver enzyme indicator, e.g. P450enzyme indicator. In another embodiment, an R_(592,940) value for atleast L_(592nm)/L_(940nm) may be used as a digestive indicator tomeasure digestive responses, such as phase 1 and phase 2 digestivestages. The biosensor 100 may also detect other types of electrolytes oranalytes, such as sodium and potassium, using similar PPG techniques. Inanother aspect, the biosensor 100 may detect which blood cell counts orconcentration levels in arterial blood flow using similar PPGtechniques.

In another aspect, abnormal cells or proteins or compounds that arepresent or have higher concentrations in the blood with persons havingcancer, may be detected using similar PPG techniques described herein atone or more other wavelengths. Thus, cancer risk may then be obtainedthrough non-invasive testing by the biosensor 100. Since the biosensor100 may operate in multiple frequencies, various health monitoring testsmay be performed concurrently. These and other aspects of the biosensor100 are described in more detail herein with clinical trial results.

FIG. 8 illustrates a logical flow diagram of an embodiment of a method800 of determining concentration levels of one or more substances. Thebiosensor 100 transmits light at one or more predetermined wavelengths.In another aspect, the biosensor 100 may also transmit light at one ormore ranges of approximately 1 nm to 50 nm wavelengths, each rangeincluding one or more predetermined wavelengths. For example, for thepredetermined wavelength 390 nm, the biosensor 100 may transmit lightdirected at skin tissue of the patient in a range of 360 nm to 410 nmincluding the predetermine wavelength 390 nm. For the predeterminedwavelength of 940 nm, the biosensor 100 may transmit light directed atthe skin tissue of the patient in a range of 920 nm to 975 nm.

The biosensor 100 detects the reflected light at 804 from the skintissue and analyzes a spectral response at the one or more predeterminedwavelengths (or ranges including the predetermined wavelengths) at 806.The absorption levels are measured over one or more cardiac cycles andsystolic and diastolic points of the spectral response are determined.Because the human pulse is typically on the order of magnitude of one 1HZ, typically the time differences between the systolic and diastolicpoints are on the order of magnitude of milliseconds or tens ofmilliseconds or hundreds of milliseconds. Thus, spectral responsemeasurements may need to be acquired at a frequency of around 10-100 Hz.

The systolic and diastolic points of the spectral response for awavelength may also be aligned with systolic and diastolic points ofanother wavelength, an arterial pulse waveform or cardiac cycle at 808.The biosensor 100 is then configured to calculate L_(λ1) and L_(λ2)values at 810. The biosensor 100 may also calculate ratio R_(λ1, λ2)values at 810. Using the determined L_(λ1) and L_(λ2) values or ratioR_(λ1,λ2) value, concentration levels or indicators of one or moresubstances may be obtained in the pulsating arterial blood flow at 812.The biosensor 100 may thus be used to non-invasively detectconcentration levels or indicators of one or more substances inpulsating arterial blood flow.

FIG. 9 illustrates a logical flow diagram of another embodiment of amethod 900 of determining concentration levels of one or moresubstances. The biosensor 100 obtains a first spectral response signalincluding a first wavelength and a second response signal including asecond wavelength at 902. In general, the first wavelength is selectedthat has a high absorption coefficient for the targeted substance whilethe second wavelength is selected that has a low absorption coefficientfor the targeted substance. Thus, it is generally desired that thespectral response for the first predetermined wavelength have a higherintensity level than the spectral response for the second predeterminedwavelength.

Each of the spectral response signals includes AC and DC componentsI_(AC+DC). A low pass filter is applied to the spectral response signalsI_(AC+DC) to isolate the DC component of the first and second spectralresponse signals I_(DC). The AC fluctuation is due to the pulsatileexpansion of the arteriolar bed due to the volume increase in arterialblood. In order to measure the AC fluctuation, measurements are taken atdifferent times and a peak detection algorithm or other means is used todetermine the diastolic point and the systolic point of the spectralresponse at 906. The systolic and diastolic measurements are compared inorder to compute the aforementioned R ratio. For example, a logarithmicfunction may be applied to the ratio of I_(AC+DC) and I_(DC) to obtainan L value for the first wavelength L_(λ1) at 908 and for the secondwavelength L_(λ2) at 910. The ratio R of the L_(λ) values may then becalculated at 912.

FIG. 10 illustrates a schematic block diagram of another embodiment of abiosensor 100 using a broad spectrum light source 1020. In one aspect,the biosensor 100 may include a broad spectrum light source 1020, suchas a white light to infrared (IR) or near IR LED 1022, that emits lightwith wavelengths from e.g. 350 nm to 2500 nm. Broad spectrum lightsources with different ranges may be implemented. In an aspect, a broadspectrum light source with a range across 100 nm wavelengths to 2000 nmrange of wavelengths in the visible, IR and/or UV frequencies. Forexample, a broadband tungsten light source for spectroscopy may be used.The spectral response of the reflected light is then measured across thewavelengths in the broad spectrum, e.g. from 350 nm to 2500 nm,concurrently. In an aspect, a charge coupled device (CCD) spectrometer1030 may be configured to measure the spectral response of the detectedlight over the broad spectrum.

The spectral response of the reflected light is analyzed for a pluralityof wavelengths, e.g. at 10 nm to 15 nm to 20 nm, incremental wavelengthsacross the wavelengths from 10 nm to 2500 nm. For example, theprocessing described with respect to FIG. 9 is performed at theplurality of wavelengths. In one aspect, the L values are calculated atincremental wavelengths, such as at 1 nm or 1.5 nm or 2 nm incrementalwavelengths. This process may be used to determine one or morewavelengths or ranges of wavelengths useful in detection for one or moresubstances in the arterial blood flow. For example, a spectral responsearound a wavelength of 500 nm may have a higher intensity. Trials maythen be conducted to determine the one or more substances in the bloodthat generates this spectral response. In another embodiment, a knownsubstance may be present in the blood and the spectral response acrossthe broad spectrum is then analyzed to determine a pattern orcorrelation of intensities of wavelengths in the spectral response tothe known substance. For example, a pattern of intensities ofwavelengths across a range of wavelengths may indicate the presence of asubstance. The intensities of the wavelengths may then be analyzed todetermine concentration levels of the substance as described in moredetail herein.

In another embodiment, the spectral response is analyzed at a set ofpredetermined wavelengths (or a range of 1 nm to 50 nm including eachpredetermined wavelength). The L values are calculated for the set ofpredetermined wavelengths using the analyzed spectral responses. Theconcentration levels of one or more substances may then be determinedbased on absorption coefficients for the one or more substances at eachof the predetermined wavelengths. The concentration levels of aplurality of substances may be determined using the spectral response ofa plurality of frequencies. The biosensor 100 may thus be used to detecta plurality of substances based on data obtained during a singlemeasurement period. The biosensor 100 may thus perform a blood panelanalysis based on in vivo arterial blood flow in a relatively shortmeasurement period of 1-5 minutes. The blood panel analysis may beperformed in a physician's office to determine results of the test whilethe patient is in the office. The biosensor 100 may thus provide bloodpanel analysis results in a 1-5 minute measurement period without a needfor blood samples and lab tests that may take hours or days or weeks toobtain.

FIG. 11A illustrates a graph of an embodiment of an output of a broadspectrum light source. The relative light intensity or power output ofthe broad spectrum light source is shown versus wavelength of the outputlight lo. The light intensity or power of the output light extends fromwavelengths of approximately 350 nm to approximately 2500 nm. The broadspectrum light source 1020 emits light with power across the wavelengthsfrom 350 nm to 2500 nm. Broad spectrum light sources with differentranges may be implemented. In an aspect, a broad spectrum light sourcewith a range across 100 nm wavelengths to 2000 nm range of wavelengthsin the visible, IR and/or UV frequencies.

FIG. 11B illustrates a graph with an embodiment of an exemplary spectralresponse of detected light 1104 across a broad spectrum, e.g. fromapproximately 10 nm to 2000 nm. In one aspect, the spectral response ofthe detected light 1104 may be analyzed at a plurality of wavelengths,e.g. at a set of predetermined wavelengths or at incrementalwavelengths. In another aspect, the spectral response of wavelengthswith a detected intensity or power exceeding a predetermined thresholdmay be analyzed. For example, in the graph shown in FIG. 11B, thespectral response at wavelengths of 200 nm, 680 nm and 990 nm (andranges of +/−20 to 50 nm around these wavelengths) exceeding a relativeintensity threshold of 20000 may be analyzed.

Embodiment—Determination of Concentration Levels at a Plurality ofWavelengths

FIG. 12 illustrates a logical flow diagram of an exemplary method 1200to determine blood concentration levels of a plurality of substancesusing the spectral response for a plurality of wavelengths. Thebiosensor 100 transmits light directed at living tissue. The light maybe across a broad spectrum or at a plurality of discrete frequencies orat a single frequency. For example, the light may be emitted using abroad spectrum light source or multiple LEDs transmitting at discretewavelengths or a tunable laser transmitting at one or more frequencies.The spectral response of light (e.g. either transmitted through theliving tissue or reflected by the living tissue) is detected at 1204.The spectral response is analyzed at a plurality of wavelengths (andranges of +/−20 to 50 nm around these wavelengths) at 1206. In oneaspect, the systolic and diastolic points are determined at theplurality of wavelengths and the L values are calculated using thesystolic and diastolic points. In one aspect, the L values aredetermined at incremental wavelengths, such as at 1 nm or 1.5 nm or 2 nmincremental wavelengths. In another aspect, the L values are calculatedfor a set of predetermined wavelengths. A ratio R value may also bedetermined using L values derived from a first spectral responseobtained for a first wavelength (and in one aspect including a range of+/−20 to 50 nm) and a spectral response obtained for a second wavelength(and in one aspect including a ranges of +/−20 to 50 nm).

Using the absorption coefficients associated with the plurality ofsubstances, the concentration levels of a plurality of substances maythen be determined. For example, the intensity of light may be due toabsorption by a plurality of substances in the arterial blood flow. Forexample,

LN(I _(1-n))=μ₁ *C ₁+μ₂ *C ₂+μ₃ *C ₃ . . . +μ_(n) *C _(n)

wherein,

I_(1-n)=intensity of light at wavelengths λ_(1-n)

μ_(n)=absorption coefficient of substance 1, 2, . . . n at wavelengthsλ_(1-n)

C_(n)=Concentration level of substance 1, 2, . . . n

When the absorption coefficients λ_(1-n) are known at the wavelengthsλ_(1-n), then the concentration levels C_(1-n) of multiple substancesmay be determined.

FIG. 13 illustrates a logical flow diagram of an exemplary method 1300to determine blood concentration levels of a single substance using thespectral response for a plurality of wavelengths. The intensity of lightat a plurality of wavelengths may be due to absorption by a singlesubstance in the arterial blood flow. For example, a single substancemay absorb or reflect a plurality of different wavelengths of light. Inthis example then,

LN(I _(1-n))=μ₁ *C+μ ₂ *C+μ ₃ *C . . . +μ _(n) C

wherein,

I_(1-n)=intensity of light at wavelengths λ_(1-n)

μ_(n)=absorption coefficient of a substance at wavelengths λ_(1-n)

C=Concentration level of a substance

When the absorption coefficients μ_(1-n) of the single substance areknown at the wavelengths λ_(1-n), then the concentration level C of thesubstance may be determined from the spectral response for each of thewavelengths (and in one aspect including a range of 1 nm to 50 nm aroundeach of the wavelengths). Using the spectral response at multiplefrequencies provides a more robust determination of the concentrationlevel of the substance.

In use, the biosensor 100 transmits light directed at living tissue at aplurality of discrete wavelengths or over a broad spectrum at 1302. Thespectral response of light from the living tissue is detected at 1304,and the spectral response is analyzed for a plurality of wavelengths(and in one aspect including a range of +/−20 to 50 nm around each ofthe wavelengths) at 1306. Then, the concentration level C of thesubstance may be determined from the spectral response for each of theplurality of wavelengths at 1308. An example for calculating theconcentration of one or more substances over multiple wavelengths may beperformed using a linear function, such as is illustrated herein below.

LN(I _(1-n))=Σ_(i=0) ^(n) μi*Ci

wherein,

I_(1-n)=intensity of light at wavelengths λ_(1-n)

μ_(n)=absorption coefficient of substance 1, 2, . . . n at wavelengthsλ_(1-n)

C_(n)=Concentration level of substance 1, 2, . . . n

FIG. 14 illustrates an exemplary graph 1400 of spectral responses of aplurality of wavelengths from clinical data using the biosensor 100. Inthis embodiment, the spectral response of a plurality of wavelengths wasmeasured using the biosensor 100 over a measurement period of almost 600seconds or approximately 10 minutes. The graph illustrates the spectralresponse for a first wavelength 1402 of approximately 940 nm, thespectral response for a second wavelength 1404 of approximately 660 nmand the spectral response for a third wavelength 1406 of approximately390 nm obtained from a first biosensor 100 measuring reflected lightfrom a first fingertip of a patient. The graph further illustrates thespectral response for a fourth wavelength 1410 of approximately 592 nmand a fifth wavelength 1412 of approximately 468 nm and the spectralresponse 1408 again at 940 nm obtained from a second biosensor measuringreflected light from a second fingertip of a patient. The spectralresponses are temporally aligned using the systolic and diastolicpoints. Though two biosensors were used to obtain the spectral responsesin this clinical trial, a single biosensor 100 may also be configured toobtain the spectral responses of the plurality of wavelengths.

Various unexpected results were determined from clinical trials usingthe biosensor 100. In one aspect, based on the clinical trials, an Rvalue obtained from the ratio L_(λ1=390nm/) and L_(λ2=940) was found tobe a predictor or indicator of diabetic risk or diabetes as described inmore detail herein. In another aspect, based on the clinical trials, theR value obtained from the ratio of L_(468nm)/L_(940nm), was identifiedas an indicator of the liver enzyme marker, e.g. P450. In anotheraspect, based on the clinical trials, the R value obtained from theratio of L_(592nm)/L_(940nm), was identified as an indicator ofdigestion phases, such as phase 1 and phase 2, in the arterial bloodflow. In another aspect, the R value from the ratio ofL_(660nm)/L_(940nm), was found to be an indicator of oxygen saturationlevels SpO₂ in the arterial blood flow. In another aspect, it wasdetermined that the biosensor 100 may determine alcohol levels in theblood using spectral responses for wavelengths at 390 and/or 468 nm. Ingeneral, the second wavelength of 940 nm is selected because it has alow absorption coefficient for the targeted substances described herein.Thus, another wavelength other than 940 nm with a low absorptioncoefficient for the targeted substances (e.g. at least less than 25% ofthe absorption coefficient of the targeted substance for the firstwavelength) may be used instead. For example, the second wavelength of940 nm may be replaced with 860 nm that has a low absorption coefficientfor the targeted substances. In another aspect, the second wavelength of940 nm may be replaced with other wavelengths, e.g. in the IR range,that have a low absorption coefficient for the targeted substances. Ingeneral, it is desired that the spectral response for the firstpredetermined wavelength have a higher intensity level than the spectralresponse for the second predetermined wavelength.

In another aspect, it was determined that other proteins or compounds,such as those present or with higher concentrations in the blood withpersons having cancer, may be detected using similar PPG techniquesdescribed herein with biosensor 100 at one or more other wavelengths.Cancer risk may then be determined using non-invasive testing over ashort measurement period of 1-10 minutes. Since the biosensor mayoperate in multiple frequencies, various health monitoring tests may beperformed concurrently. For example, the biosensor 100 may measure fordiabetic risk, liver enzymes, alcohol levels, cancer risk or presence ofother analytes within a same measurement period using PPG techniques.

FIG. 15 illustrates a logical flow diagram of an exemplary method 1500to determine an absorption coefficients μ of a substance at a wavelengthλ. The concentration level of a substance in arterial blood is obtainedusing a known method at 1502. For example, blood may be extracted atpredetermined intervals during a time period and a blood gas analyzermay be used to measure a concentration level of a substance. Thebiosensor 100 emits light at a wavelength (and in one aspect for a rangeof 1 nm-50 nm around the wavelength) and detects a spectral response forthe wavelength (and in one aspect for a range of 1 nm-50 nm around thewavelength). The spectral response for the predetermined wavelength isanalyzed at 1506. The intensity of the detected light is determined. Theintensity of the detected light is compared to the known concentrationlevel of the substance at 1508. The absorption coefficient for thesubstance may then be determined using the Beer-Lambert equationsdescribed herein at 1510.

The above process may be repeated at one or more other frequencies at1512. For example, as described herein, the spectral analysis over arange or at multiple frequencies may be analyzed to determine one ormore frequencies with a higher intensity or power level in response to aconcentration level or presence of the substance. Thus, one or morefrequencies may be analyzed and identified for detection of thesubstance, and the absorption coefficient for the substance determinedat the one or more frequencies.

In another embodiment, the concentration level of a substance may beobtained from predetermined values obtained through experimentation. Forexample, in a calibration phase, a correlation table may be compiledthrough experimentation that includes light intensity values I_(1-n) atone or more wavelengths λ_(1-n) and a corresponding known concentrationlevel for the substance for the light intensity values. In use, thebiosensor 100 detects a spectral response and determines the lightintensity values I_(1-n) at one or more wavelengths λ_(1-n). Thebiosensor 100 then looks up the detected light intensity values I_(1-n)in the correlation table to determine the concentration level of thesubstance.

FIG. 16 illustrates a schematic block diagram of a spatial distributionof light intensity amplitude for different forces of contact between thebiosensor 100 and a skin surface. Spatial distribution of the PPGamplitude for different forces of contact was measured between a glasstable and skin of one of the subjects during steps a, b and c. Theresults of the experiment are illustrated in FIG. 16 wherein the spatialdistributions of the PPG-amplitude obtained during the steps a, b, and care presented respectively. The mechanical contact of the glass with thesubject's skin substantially increases the amplitude of the observed PPGsignal. Moreover, by increasing the force of the contact, the amplitudeof the PPG signal and the area with elevated PPG amplitude is increased.As such, compression enhances the PPG signal. So compression of thebiosensor 100 against the skin of a patient may be implemented duringuse of biosensor 100 in its one or more form factors. The article byKamshilin A A, Nippolainen E, Sidorov I S, et al. entitled “A new lookat the essence of the imaging photoplethysmography” in ScientificReports, May 21, 2015, 5:10494 and doi:10.1038/srep10494 includesfurther details on spatial distribution of PPG intensity amplitude fordifferent forces of contact, and is hereby incorporated by referenceherein.

Embodiment—Biosensor Form Factors

FIG. 17A illustrates an exemplary embodiment of a form factor of thebiosensor 100. In an embodiment, the biosensor 100 is implemented on awearable patch 1700. The wearable patch 1700 may include an adhesivebacking to attach to a skin surface of a patient, such as on a hand,arm, wrist, forehead, chest, abdominal area, or other area of the skinor body or living tissue. Alternatively, the wearable patch 1700 may beattached to the skin surface using adhesive tape. A flexible cable 1702may be used to attach an optical head 1704 of the wearable patch 1700 tothe other components of the biosensor 100, such as the wirelesstransceiver 106 and battery 108. Thus, during a magnetic resonanceimaging (MRI) test when metal needs to be minimal, the battery 108 andtransceiver 106 may be temporarily removed. In addition, the flexiblecable 1702 may be used to open the biosensor 100 to replace the battery108.

FIG. 17B illustrates an exemplary embodiment of another form factor ofthe biosensor 100. In this embodiment, the biosensor 100 is implementedon an arm band 1710. The arm band 1710 may be configured with anadjustable band for placement on an arm, wrist, on one or more fingers,around a leg, etc. In general, the arm band 1710 should be secured suchthat the PPG circuit 110 is positioned to direct light towards the skinsurface.

FIG. 18A illustrates an exemplary embodiment of another form factor ofthe biosensor 100. In this embodiment, the biosensor 100 may be coupledto an attachable bandaid 1800. The attachable bandaid 1800 may beattached via adhesive or adhesive tape to a skin surface of the patient,e.g. finger, forehead, arm, stomach, leg, wrist, etc.

FIG. 18B illustrates an exemplary embodiment of another form factor ofthe biosensor 100. In this embodiment, the biosensor 100 is configuredin an earpiece 1810. The earpiece 1810 includes an earbud 1812. Thebiosensor 100 is configured to transmit light into the ear canal fromone or more optical fibers in the ear bud 1812 and detect light from theear canal using one or more optical fibers.

FIG. 19A illustrates an exemplary embodiment of another form factor ofthe biosensor 100. In this embodiment, the biosensor 100 is configuredto attach to a finger or fingertip using finger attachment 1902. Thefinger attachment 1902 is configured to securely hold a finger that isinserted into the finger attachment 1902. A display 1900 is implementedon the biosensor 100 with a graphical user interface (GUI) that displaysbiosensor data. For example, in use, the biosensor 100 measures bloodglucose levels using the PPG circuit 110. The blood glucose levels arethen displayed using the GUI on the display 1900. The PPG circuit mayalso measure other patient vitals that are displayed on the display1900, such as oxygen saturation levels, temperature, blood alcohollevels, digestive response, calorie intake, white blood cell count,electrolyte or other blood analyte concentrations, liver enzymes, etc.The biosensor 100 may thus provide biosensor data non-invasively withouta blood sample.

FIG. 19B illustrates an exemplary embodiment of another form factor ofthe biosensor 100. In this embodiment, the biosensor 100 is configuredto attach to a finger or fingertip using finger attachment 1906. Thefinger attachment 1906 includes the PPG circuit 110 and is configured tosecurely hold a finger that is inserted into the finger attachment 1906.The finger attachment 1906 may be implemented within the same encasementas the other components of the biosensor 100 or be communicativelycoupled either through a wired or wireless interface to the othercomponents of the biosensor 100. A display 1908 is implemented for thebiosensor 100 with a graphical user interface (GUI) that displaysbiosensor data including blood glucose levels.

The biosensor 100 may be configured to be attached to an ear lobe orother body parts in other form factors. In addition, one or morebiosensors 100 in one or more form factors may be used in combination todetermine biosensor data at one or more areas of the body.

In these or other form factors, the biosensor 100 may store a uniquepatient identification 172 that is generally included as a barcode oncurrent armbands. The biosensor 100 may also store patient health datameasured by the biosensor 100 or EMR 170 of the patient that may be usedin one or more applications or systems in the health care chain of apatient. For example, the biosensor 100 is programmed with a uniquepatient identification 172 that is assigned to a patient duringadmission to a hospital and is used for tracking of the patient throughthe transceiver 106 of the biosensor 100. As such, a separate scanner isnot needed to track a patient or scan an arm band. The biosensor 100monitors the patients vitals as part of the care management of thepatient. The patients vitals are used in data analytics for diagnosis,treatment options, monitoring, etc. The patient vitals may be includedin the patient EMR 170 and otherwise used for patient health. Thebiosensor 100 may also communicate with inventory management. Forexample, when a medicine is provided to a patient, this information ofthe medicine and dosage may be provided to the inventory managementsystem. The inventory management system is then able to adjust theinventory of the medicine. The biosensor 100 may thus have these and/oradditional applications.

Embodiment—EMR Network

FIG. 20 illustrates a schematic block diagram of an embodiment of anexemplary network 2000 in which the the biosensor 100 described hereinmay operate. The exemplary network 2000 may include a combination of oneor more networks that are communicatively coupled, e.g., such as a widearea network (WAN) 2002, a wired local area network (LAN) 2004, awireless local area network (WLAN) 2006, or a wireless wide area network(WAN) 2008. The wireless WAN 1228 may include, for example, a 3G or 4Gcellular network, a GSM network, a WIMAX network, an EDGE network, aGERAN network, etc. or a satellite network or a combination thereof. TheWAN 1222 includes the Internet, service provider network, other type ofWAN, or a combination of one or more thereof. The LAN 2004 and the WLANs20066 may operate inside a home 2016 or enterprise environment, such asa physician's office 2018, pharmacy 2020 or hospital 2022 or othercaregiver.

The biosensor 100 may communicate to one or more user devices 2010, suchas a smart phone, laptop, desktop, smart tablet, smart watch, or anyother electronic device that includes a display for illustrating thepatient's vitals. In one aspect, the user device 2010 or biosensor 100may communicate the patient's vitals to a local or remote monitoringstation 2012 of a caregiver or physician.

One or more biosensor 100 s are communicatively coupled to an EMRapplication server 2030 through one or more of user devices and/or theexemplary networks in the EMR network 2000. The EMR server 2030 includesa network interface card (NIC) 2032, a server processing circuit 2034, aserver memory device 2036 and EMR server application 2038. The networkinterface circuit (NIC) 1202 includes an interface for wireless and/orwired network communications with one or more of the exemplary networksin the EMR network 1220. The network interface circuit 1202 may alsoinclude authentication capability that provides authentication prior toallowing access to some or all of the resources of the EMR applicationserver 1200. The network interface circuit 1202 may also includefirewall, gateway and proxy server functions.

One or more of the biosensors 100 are communicatively coupled to an EMRapplication server 1200 through one or more of the exemplary networks inthe EMR network 1220. The EMR application server 1200 includes a networkinterface circuit 1202 and a server processing circuit 1204. The networkinterface circuit (NIC) 1202 includes an interface for wireless and/orwired network communications with one or more of the exemplary networksin the EMR network 1220. The network interface circuit 1202 may alsoinclude authentication capability that provides authentication prior toallowing access to some or all of the resources of the EMR applicationserver 1200. The network interface circuit 1202 may also includefirewall, gateway and proxy server functions.

The EMR application server 1200 also includes a server processingcircuit 2034 and a memory device 2036. For example, the memory device2036 is a non-transitory, processor readable medium that storesinstructions which when executed by the server processing circuit 2034,causes the server processing circuit 2034 to perform one or morefunctions described herein. In an embodiment, the memory device 2036stores a patient EMR 170 that includes biosensor data and historicaldata of a patient associated with the patient ID 172.

The EMR application server 1200 includes an EMR server application 2038.The EMR server application 2038 is operable to communicate with thebiosensors 100 and/or user devices 2010 and monitoring stations 2012.The EMR server application 2038 may be a web-based application supportedby the EMR application server 2030. For example, the EMR applicationserver 2030 may be a web server and support the EMR server application2038 via a website. In another embodiment, the EMR server application2038 is a stand-alone application that is downloaded to the user devices2010 by the EMR application server 2030 and is operable on the userdevices 2010 without access to the EMR application server 2030 or onlyneeds to accesses the EMR application server 2030 for additionalinformation and updates.

In use, the biosensors 100 may communicate patient's biosensor data tothe EMR application server 2030. A biosensor 100 may be programmed witha patient identification 172 that is associated with a patient's EMR170. The biosensor 100 measures the patient's vitals, such as heartrate, pulse, blood oxygen levels, blood glucose levels, etc. and mayalso control an integrated or separate drug delivery system toadminister medications to the patient. The biosensor 100 is configuredto transmit the patient vitals to the EMR application server 2030. TheEMR server application 2038 updates an EMR 170 associated with thepatient identification 172 with the patient vitals.

The EMR application server 2030 may also be operable to communicate witha physician's office 2018 or pharmacy 2016 or other third party healthcare provider over the EMR network 2000 to provide biosensor data andreceive instructions on dosages of medication. For example, the EMRserver application 2038 may transmit glucose level information, heartrate information or pulse rate information or medication dosages orblood concentration levels of one or more relevant substances to aphysician's office 2018. The EMR server application 2038 may also beconfigured to provide medical alerts to notify a user, physician orother caregiver when vitals are critical or reach a certainpredetermined threshold.

The EMR server application 1408 may also receive instructions from adoctor's office, pharmacy 2016 or hospital 2022 or other caregiverregarding a prescription or administration of a dosage of medication.The EMR server application 2038 may then transmit the instructions tothe biosensor 100. The instructions may include a dosage amount, rate ofadministration or frequency of dosages of a medication. The biosensor100 may then control a drug delivery system to administer the medicationautomatically as per the transmitted instructions.

Embodiment—Interoperability of Biosensors and Other Devices

FIG. 21A illustrates a schematic block diagram of an embodiment of anetwork illustrating interoperability of a plurality of biosensors 100.A plurality of biosensors 100 may interface with a patient andcommunicate with one or more of the other biosensor 100 s. Thebiosensors 100 may communicate directly or communicate indirectlythrough a WLAN or other type of network as illustrated in the Network2000 of FIG. 20. For example, a first biosensor 100 a may include a PPGcircuit 110 configured to detect a blood glucose level. For betterdetection, the biosensor 100 a is positioned on a wrist. A secondbiosensor 100 b may include a drug delivery system 116 configured toadminister insulin to the patient 2100 and is positioned on an abdominalarea of the patient 2100. In use, the first biosensor 100 a continuouslymonitors blood glucose levels and then communicates either directly orindirectly the detected levels to the second biosensor 100 b. The secondbiosensor 100 b then administers a dosage of insulin at anadministration rate and/or frequency rate in response to the detectedblood glucose levels.

In another example, one or more biosensor 100 s may communicate directlyor indirectly with one or more other types of medical devices 2102interfacing with a same patient, such as a first medical device 2100 aand a second medical device 2100 b. The first medical device 2102 a mayinclude an insulin pump, e.g. on body insulin pump or catheter tethereddrip system. In use, the biosensor 100 a monitors glucose and/or insulinindicators or concentration levels in the patient using the PPG circuit110. In response to the detected glucose and/or insulinconcentration/indicators, the biosensor 100 a communicates eitherdirectly or indirectly administration instructions to the first medicaldevice 2102 a. The administration instructions may include dosageamount, administration rate and/or frequency rate. In response to theadministration instructions, the first medical device 2102 a administersan insulin infusion to the patient. The first biosensor 100 a maycontinuously monitor glucose/insulin indicators or concentration levelsand provide automatic instructions to the the first medical device 2102a for the administration of insulin.

In another example, a plurality of biosensors 100, such as the firstbiosensor 100 a and the second biosensor 100 b, may be positioned on apatient to monitor an ECG of the patient. The biosensors 100 maycommunicate the ECG measurements directly or indirectly to each other togenerate an electrocardiogram. The electrocardiogram is transmitted toan EMR application server 2030 or monitoring station 2012 or to a userdevice 2010. Based on the electrocardiogram, a doctor or user mayprovide instructions to the second medical device 2102 b. For example,the second medical device 2102 b may include a Pacemaker or drugdelivery system.

In another example, the biosensor 100 a may include a PPG circuit 110configured to detect alcohol levels in arterial blood flow. The userdevice 2010 may include a locking system installed in an ignition systemof a vehicle. In order to start the vehicle, the the biosensor 100 adetects the blood alcohol concentration (BAC) of the patient. Then thebiosensor 100 a determines whether the blood alcohol concentration (BAC)is above or below a preset legal limit. If it is below this limit, thebiosensor 100 a communicates an instruction to the user device 2010 tounlock the ignition to allow starting of the vehicle. If it is above thelimit, the biosensor 100 a instructs the user device 2010 to lock theignition to prevent starting of the vehicle. Since the biosensor 100 ais directly testing the blood alcohol levels, the biosensor 100 a may bemore accurate and convenient than current breathe analyzers.

Embodiment—Adjustments in response to Positioning of the Biosensor

FIG. 21B illustrates a logical flow diagram of an embodiment of a method2110 for adjusting operation of the biosensor 100 in response to aposition of the biosensor 100. The biosensor 100 may be positioned ondifferent parts of a patient that exhibit different characteristics. Forexample, the biosensor 100 may be positioned on or attached to variousareas of the body, e.g. a hand, a wrist, an arm, forehead, chest,abdominal area, ear lobe, fingertip or other area of the skin or body orliving tissue. The characteristics of underlying tissue vary dependingon the area of the body, e.g. the underlying tissue of an abdominal areahas different characteristics than the underlying tissue at a wrist. Theoperation of the biosensor 100 may need to be adjusted in response toits positioning due to such varying characteristics of underlyingtissue.

The biosensor 100 is configured to obtain position information on apatient at 2112. The position information may be input from a userinterface. In another aspect, the biosensor 100 may determine itspositioning, e.g. using the activity monitoring circuit 114 and/or PPGcircuit 110. For example, the PPG circuit 110 may be configured todetect characteristics of underlying tissue. The biosensor 100 thencorrelates the detected characteristics of the underlying tissue withknown or predetermined characteristics of underlying tissue (e.g.measured from an abdominal area, wrist, forearm, leg, etc.) to determineits positioning. Information of amount and types of movement from theactivity monitoring circuit 114 may be used as well in the determinationof position.

In response to the determined position and/or detected characteristicsof the underlying tissue, the operation of the biosensor 100 is adjustedat 2114. For example, the biosensor 100 may adjust operation of the PPGcircuit 110. The article, “Optical Properties of Biological Tissues: AReview,” by Steven L. Jacques, Phys. Med. Biol. 58 (2013), which ishereby incorporated by reference herein, describes wavelength-dependentbehavior of scattering and absorption of different tissues. The PPGcircuit 110 may adjust a frequency or wavelength in detection of aconcentration level of a substance based on the underlying tissue. ThePPG circuit 110 may adjust an absorption coefficient when determining aconcentration level of a substance based on Beer-Lambert principles dueto the characteristics of the underlying tissue. Other adjustments mayalso be implemented depending on predetermined or measuredcharacteristics of the underlying tissue.

Adjustments to the activity monitoring circuit 114 may need to be madedepending on positioning as well. For example, the type and level ofmovement detected when positioned on a wrist of a patient may vary fromthe type and level of movement when positioned on an abdominal area ofthe patient. In another aspect, the biosensor 100 may adjustmeasurements from the temperature sensor 112 depending on placement ofthe patient, e.g. the sensor array measurements may vary from a wrist orforehead.

The biosensor 100 is thus configured to obtain position information andperform adjustments to its operation in response to the positioninformation.

Embodiment—Diabetic Parameter Measurements

Clinical data obtained using the biosensor 100 is now described herein.The biosensor 100 was used to monitor concentration levels or indicatorsof one or more substances in the blood flow of the patient in theclinical trials over a measurement time period. For example, thebiosensor 100 was used in the clinical trials to non-invasively detectdiabetic parameters, such as insulin response over time, nitric oxide(NO) levels, glucose levels, and predict diabetic risk or diabeticprecursors, in pulsatile arterial blood flow. The biosensor 100 was alsoused to detect blood alcohol levels in pulsatile arterial blood flow.The biosensor 100 was also used to detect digestive parameters, such asdigestion phase 1 and 2 responses. The biosensor 100 also detected heartrate and blood oxygen saturation levels in the clinical trials.

FIG. 22 illustrates a schematic drawing of an exemplary embodiment ofresults of clinical data 2200 obtained using the biosensor 100 from afirst patient. This first patient is a 42 year old female with no knowndiagnosis of diabetes. A biosensor 100 is placed on at least one fingerof the first patient and the spectral response is measured over theleast three wavelengths at 390 nm, 660 nm and 940 nm (and also in rangeof 1 nm to 50 nm). The graph 2006 illustrates the spectral response orfrequency spectrum data obtained for the three wavelengths. The spectralresponse in graph 2206 shows the frequency versus the relative intensitymeasured by the biosensor 100. The graph 2202 illustrates the L valueobtained from the spectral responses for each of the three wavelengthsobtained, e.g., from the spectral response data shown in graph 2206. TheL value obtained for the three wavelengths is a measured response fromthe pulsating arterial blood flow in the patient.

The graph 2208 illustrates the calculated Ratio R forR₁=L_(390nm)/L_(940nm) and R₂=L_(390nm)/L_(660nm). In one aspect, basedon unexpected results from clinical trials, it was determined that aratio R value obtained at approximately L_(λ1)=390 nm and L_(λ2)=940 nmis useful as a predictor or indicator of diabetic risk or diabetes. Forexample, during experimental clinical trials, spectral responses wereobtained during a measurement period over a 1-2 minute time period forwavelengths of 390 nm and 940 nm (and also in ranges of 1 nm to 50 nmincluding these wavelengths). An R value was obtained based on thespectral responses. From the unexpected results of the clinical trials,an R value obtained during a period of fasting, e.g. prior to ingestionof food or liquids, of less than 1 (e.g., approximately 0.5) indicatedthat a person has diabetes or early onset of diabetes. An R value of 2or above indicated that a person has a lower risk of a diabetesdiagnosis. An R value in the 5-6 range indicated no current risk ofdiabetes. For example, as shown in graph 2208, the R value obtained forL_(λ1)=390 nm and L_(λ2)=940 nm has an average value greater than 5 inthis first patient without a diabetes diagnosis.

FIG. 23 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2300 obtained using the biosensor 100 fromthe first patient. The graph 2302 illustrates the heart rate obtainedover a measurement period of 900 seconds. The graph 2304 illustrates theoxygen saturation level SpO₂ obtained over the measurement period of 900seconds.

The graph 2306 illustrates an insulin response measured in the arterialblood flow of the patient over a measurement period of 900 seconds. Thegraph illustrates the Ratio R for approximately L_(390nm)/L_(940nm), forapproximately L_(660nm)/L_(940nm), for approximatelyL_(466nm)/L_(940nm), and for approximately L_(582nm)/L_(940nm). Inunexpected results, the Ratio R value for L_(390nm)/L_(940nm) 2310between 0 and 200 seconds is seen to correlate with the base insulinresistance factor, e.g. the base insulin concentration levels afterfasting for 2-8 hours. At approximately, 200 seconds, the patientconsumed a high sugar substance, e.g. a candy bar. In unexpectedresults, the insulin response 2308 of the patient is obtained from thebiosensor data. In particular, the Ratio R for approximatelyL_(390nm)/L_(940nm) shows the increase in insulin response 2308 from thebase insulin resistance factor 2310 in the pulsating arterial blood flowstarting at approximately 600 seconds in response to the consummation ofthe high sugar substance. The Ratio R for approximatelyL_(390nm)/L_(940nm) has a value between 4 and 6 in the healthy patientwithout a diagnosis of diabetes in response to the ingestion of the highsugar substance.

Graph 2312 illustrates the L values obtained from the spectral responsesfor the four wavelengths, L_(940nm), L_(660nm), L_(390nm), L_(582nm),and L_(463nm) over the measurement period of 900 seconds. The glucoseresponse from the consummation of the high sugar substance is startingat approximately 600 seconds. In particular, in unexpected results, itis believed that nitric oxide NO levels in the arterial blood flow isbeing measured at least in part by the biosensor 100 using the spectralresponse for the wavelength 390 nm (and 1 nm-50 nm range around 390 nm).The spectral response is responsive to nitric oxide (NO) concentrationlevels in the blood. As such, the L_(390nm) values may be used todetermine nitric oxide (NO) concentration levels in the pulsating bloodflow.

In addition, insulin in the blood generates NO as it penetrates bloodvessel walls. The NO is released as a gas before attaching to one ormore hemoglobin type molecules. Since at least part of the NO gasconcentration is in a gaseous form in the arterial blood flow, the NO inthe gaseous form will dissipate prior to measurement from in vitro bloodsamples. As such, the complete NO concentration levels may not bemeasured using in vitro blood samples, e.g. from a finger prick. Thus,the biosensor 100 measurements, e.g. using the spectral response andcalculated L values at 390 nm, are the first time NO levels in arterialblood flow have been measured in vivo. These unexpected results ofmeasuring nitric oxide NO concentration levels in pulsating arterialblood flow are obtained non-invasively and continuously over ameasurement period using the biosensor 100.

From the clinical trials performed, it has been determined that themeasured NO levels are an indication of insulin response and bloodglucose concentration levels in the blood. The R value derived fromL_(390nm)/L_(940nm) may thus be used as an indicator of insulin responseand diabetic risk as well as vascular health. These unexpected resultshave advantages in early detection of diabetic risk and easier,non-invasive monitoring of insulin resistance and blood glucose levels.The biosensor 100 may display the R value or an analysis of the diabeticrisk based on the R value. In one aspect, the biosensor 100 may display,no diabetic risk based on R values of 5 or greater. In another aspect,the biosensor 100 may display, low diabetic risk based on R values of2-5. In another aspect, the biosensor 100 may display, high diabeticrisk based on an R values of 1-2. In another aspect, the biosensor 100may display, diabetic condition detected based on an R value less thanone.

FIG. 24 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2400 obtained using the biosensor 100 from asecond patient. The second patient was a 65 year old male with a knowndiagnosis of type 1 diabetes. The graph 2402 illustrates the heart rateobtained over a measurement period of approximately 135 minutes. Thegraph 2404 illustrates the oxygen saturation level SpO2 obtained overthe measurement period of 135 minutes.

The graph 2406 illustrates an insulin response 2410 measured in thearterial blood flow of the patient over a measurement period of 135minutes. The graph illustrates the Ratio R for approximatelyL_(390nm)/L_(940nm), for approximately L_(660nm)/L_(940nm), forapproximately L_(466nm)/L_(940nm), and for approximatelyL_(582nm)/L_(940nm). In unexpected results, the Ratio R forapproximately L_(390nm)/L_(940nm) correlates with a base insulinresistance factor shown prior to approximately 200 seconds. Atapproximately, 200 seconds, the patient consumed a high sugar substance,e.g. a glucose drink. In unexpected results, the insulin response 2410of the patient is obtained from the biosensor data. In particular, theRatio R for approximately L_(390nm)/L_(940nm) shows the minimal insulinresponse 2410 in the patient with diabetes after the consummation of theglucose drink. The R value for L_(390nm)/L_(940nm) remains below a valueof 1 even after the consummation of the glucose drink indicating thelack of generation of natural insulin by the patient. At approximately4500 seconds or 75 minutes, insulin is administered to the patientthrough two injections. The graph 2406 illustrates the increase in the Rvalue due to the increase in insulin response 2410 from the injectionsafter 4500 seconds. The Ratio R for approximately L_(390nm)/L_(940nm)still remains low with a value between 2 and 4 even after the insulininjections in the patient with diabetes.

Graph 2412 illustrates the L values for the four wavelengths, L_(940nm),L_(660nm), L_(390nm), L_(582nm), and L_(463nm) over the measurementperiod of 1000 seconds. The graph of L_(390nm) 2408 shows no increase ininsulin levels until after the insulin injections at 75 minutes. Inspecific, the L_(390nm) shows particularly sensitivity in themeasurement of the base insulin resistance factor measured after fastingand the insulin response measured after caloric intake.

FIG. 25 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2500 obtained using the biosensor 100 fromthe second patient. At predetermined time periods of about 15 minutes,blood glucose level (BGL) was measured using a known method and the BGLmeasurements plotted. The plotted measurements were interpolated togenerate a polynomial showing the approximate BGLs 2504 in mg/dl units.The biosensor 100 obtained measurements over the same time period toderive the Ratio R for approximately L_(390nm)/L_(940nm) 2502, as shownon the graph as well.

In this clinical trial, the R value for L_(390nm)/L_(940nm) has a lowbase insulin resistance factor 2504 of less than 1 (in an R value rangefrom 0-8) indicating a diabetic condition in the patient. Afterconsumption of a high sugar substance at around 200 seconds, an insulinresponse 2510 is seen at approximately 232 seconds. It seems that theL_(390nm) is measuring NO levels in the arterial blood flow. As insulinis generated in the body, it reacts with blood vessels to generate NOgas. The NO gas bonds to hemoglobin and is transported in the bloodstream. The NO is thus a good indicator of a base insulin resistancefactor after fasting and an insulin response after caloric intake.

The ratio R values may also be correlated with blood glucose levels(BGL) using the graph or using a similar table or other correlationmethod. For example, the ratio R for L_(390nm)/L_(940nm) with a value of1.75 is correlated to a BGL of about 150 mG/DL using the graph. The Rvalue for L_(390nm)/L_(940nm) may thus be used to show a base insulinresistance factor 2508 insulin response 2510 as well as obtain bloodglucose levels for the patient.

In addition, nitric oxide NO generation helps hemoglobin in the uptakeof oxygen. Thus, the NO measurements, such as the R value forL_(390nm)/L_(940nm), are also a good indicator of vascular health.

FIG. 26 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2600 obtained using the biosensor 100 from athird patient. The third patient is a 37 year old female with a knowndiagnosis of Type 1 diabetes. At predetermined time periods of about 15minutes, blood glucose levels (BGL) were measured using a known methodand the BGL measurements plotted. The plotted measurements wereinterpolated to generate a polynomial showing the approximate BGL 2604in mg/dl units. The biosensor 100 obtained measurements over the sametime period to derive the Ratio R for approximately L_(390nm)/L_(940nm)2602, as shown on the graph as well.

In this clinical trial, the insulin resistance level or R value forL_(390nm)/L_(940nm) measured prior to eating has a low baseline value ofless than 1 indicating a diabetic condition. In unexpected results, thebase insulin resistance factor 2606 for the R value atL_(390nm)/L_(940nm) is seen as less than 0.8. Thus, from unexpectedclinical results, it is determined that a base insulin resistance factoror R value for L_(390nm)/L_(940nm) of less than 1 from an R value rangeof 0-8 indicates a diabetic condition. After consumption of a high sugarsubstance, insulin response is seen from 1-191 seconds.

From the clinical trials, it seems that the L_(390nm) is measuring NOlevels in the arterial blood flow. As insulin is generated in the body,it reacts with blood vessels to generate NO gas. The NO gas bonds tohemoglobin and is transported in the blood stream. The R value forL_(390nm)/L_(940nm) measures the NO levels in the pulsating arterialblood flow and thus provides a good indicator of BGLs, base insulinresistance factor and insulin response after caloric intake. The BGLsmay be obtained from the R values using the graph 2600 or a similartable that correlates the R value with known BGL measurements for thepatient.

FIG. 27 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2700 obtained using the biosensor 100 from afourth patient. The fourth patient is a 59 year old male with a knowndiagnosis of Type 2 diabetes. At predetermined time periods of about 15minutes, blood glucose level (BGL) was measured using a known method ofa blood glucose meter (BGM) using blood from finger pricks. The BGMglucose measurements 2704 are plotted. The plotted measurements wereinterpolated to generate a polynomial 2706 showing the approximate BGMglucose measurements over time in mG/DL units. The biosensor 100obtained measurements over the same time period to derive the Ratio Rfor approximately L_(390nm)/L_(940nm) 2702, as shown on the graph aswell.

In this clinical trial, the base insulin resistance factor 2708 measuredprior to eating has a low baseline value of about 0.5 indicating adiabetic condition. In unexpected results, the base insulin resistancefactor or R value for L_(390nm)/L_(940nm) of less than 1 (in an R valuerange of 0-8) thus seems to indicate a diabetic condition from theclinical trial results. After consumption of a high sugar substance,insulin response 2710 is seen after about 7 minutes. The blood glucoselevels may be obtained from the R values using the graph 2700 or asimilar calibration table that correlates the R value with known BGLmeasurements for the patient. The calibration table may be generated fora specific patient or may be generated from a sample of a generalpopulation. It is determined that the R values should correlate tosimilar BGL measurements across a general population. Thus, thecalibration table may be generated from testing of a sample of a generalpopulation.

From the unexpected results of the clinical trials, an R value of lessthan 1 (in an R value range of 0-8) indicated that a person has diabetesor early onset of diabetes. An R value of 5 (in an R value range of 0-8)or above indicated that a person has no diabetic condition. For example,as shown in graph 2208, the base insulin resistance factor measuredusing an R value of approximately L_(390nm)/L_(940nm) has generally anaverage value greater than 5 in the first patient without a diabetesdiagnosis. The base insulin resistance factor measured using an R valueof approximately L_(390nm)/L_(940nm) was generally an average value lessthan 1 (in an R value range from 0-8) in the other patients with adiabetes diagnosis of either Type 1 or Type II. The base insulinresistance factor measured using an R value in the 1-2 (in an R valuerange from 0-8) range indicated a high risk of diabetes and need forfurther testing.

It seems that the L_(390nm) is measuring NO levels in the arterial bloodflow. As insulin is generated in the body, it reacts with blood vesselsto generate NO gas. The NO gas bonds to hemoglobin and is transported inthe blood stream. The NO is thus a good indicator of a base insulinresistance factor after fasting and an insulin response after caloricintake.

From the clinical trials, it seems that the NO levels are reflected inthe R values obtained from L_(390nm)/L_(940nm). Based on the clinicaltrials and R values obtained in the clinical trials, it is determinedthat a base insulin resistance factor of less than 1 corresponds to anNO concentration level of at least less than 25% of average NO levels.For example, average NO levels are determined by sampling a generalpopulation of persons without diabetes or other health conditionsaffecting NO levels. From the clinical trials, an R value correlating toa base insulin factor of less than 1 indicates that the NO levels are ina range of 25% to 50% less than average NO levels. After fasting, aperson with a diabetic condition will have low NO concentration levelsthat are at least 25% less than average NO levels due to the low levelof insulin in the blood. Thus, an NO concentration level of at leastless than 25% of normal ranges of NO concentration levels indicates adiabetic condition (e.g., the NO levels corresponding to R value lessthan 1 in this clinical trial). Thus, a base insulin resistance factorof less than 1 correlates to at least less than 25% of average NO levelsof a sample population and indicates a diabetic condition.

Based on the clinical trials and R values obtained in the clinicaltrials, it is determined that a base insulin resistance factor in therange of 2-8 corresponds to average NO concentration levels. Thus, abase insulin resistance factor (e.g. in the range of 2-8) correlates toan average NO level of a sample population and little to no diabeticrisk.

Based on these unexpected results, in one aspect, the biosensor 100 maydisplay or transmit, e.g. to a user device or monitoring station, orotherwise output an indicator of the diabetic risk of a patient based onthe R value. For example, the biosensor 100 may output no diabetic riskbased on an obtained R value for a patient of 5 or greater. In anotheraspect, the biosensor 100 may output low diabetic risk based on anobtained R value of 2-5. In another aspect, the biosensor 100 may outputhigh diabetic risk based on an obtained R values of 1-2. In anotheraspect, the bio sensor 100 may output diabetic condition detected basedon an R value less than one. In the clinical trials herein, the R valuewas in a range of 0-8. Other ranges, weights or functions derived usingthe R value described herein may be implemented that changes thenumerical value of the R values described herein or the range of the Rvalues described herein. In general, from the results obtained herein,an R value corresponding to at least the lower 10% of the R value rangeindicates a diabetic condition, an R value in the lower 10% to 25% ofthe R value range indicates a high risk of diabetes, an R value in the25% to 60% range indicates a low risk of diabetes, and an R valuegreater than 60% indicates no diabetic condition.

The R value of L_(390nm)/L_(940nm) may be non-invasively and quickly andeasily obtained using the biosensor 100 in a physician's office or otherclinical setting or at home. In one aspect, the R value may be used todetermine whether further testing for diabetes needs to be performed.For example, upon detection of a low R value of less than 1, a clinicianmay then determine to perform further testing and monitoring, e.g. usingglucose ingestion tests over a longer period of time or using thebiosensor 100 over a longer period of time or other type of testing.

Embodiment—Blood Alcohol Level Measurements

FIG. 28 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2800 obtained using the biosensor 100 from afifth patient. In this trial, the fifth patient was a 55 year old malethat ingested a shot of whiskey at approximately 7 seconds. Thebiosensor 100 was used to measure an indicator of blood alcohol levelsover a measurement period of approximately 271 seconds using awavelength of approximately 468 nm. The graph illustrates the valuesobtained for ratio R=L_(468nm)/L_(940nm) 2802 over the measurementperiod. The biosensor 100 was able to detect the increase in the bloodalcohol levels over the measurement period. The ratio R values 2802 maybe correlated with blood alcohol levels using a table or graph thatassociates the R values 2802 with blood alcohol levels. For example, thetable or graph may be obtained through blood alcohol levels measuredfrom blood drawn at preset intervals (such as every 1-5 minutes) duringa measurement period (such as 1-5 hours) and interpolating the resultingmeasurements. The interpolated measurements are then associated with themeasured ratio R values 2802 over the same measurement period. Ingeneral, the ratio R values 2802 are consistent with an approximatemeasured blood alcohol level in subsequent clinical trials for apatient. The calibration of measured blood alcohol levels to ratio Rvalues 2802 may thus only be performed once for a patient. In anotheraspect, the calibration table may be generated using testing of a sampleof a general population. It is determined that the R values shouldcorrelate to similar BAL measurements across a general population. Thus,the calibration table may be generated from testing of a sample of ageneral population.

Embodiment—Digestive Stage and Caloric Intake Measurements

FIG. 29 illustrates a schematic drawing of another exemplary embodimentof results of clinical data 2900 obtained using the biosensor 100 fromthe fifth patient. In this trial, the fifth patient ingested whiskey atapproximately 13 seconds. The biosensor 100 was used to measure thedigestive stages over a measurement period of approximately 37 minutesusing a wavelength of approximately 390 nm to track the blood glucoselevels. The graph illustrates the values for L_(390nm) 2902 obtainedover the measurement period. The biosensor 100 was able to detect thedigestive stage 1 2904 and digestive stage 2 2906 based on the obtainedvalues for L_(390nm). The first digestive stage 1 2904 is indicated byan initial spike around 20 seconds as blood rushes to the stomach to aidin digestion. The second digestive stage 2 is indicated by a later, moreprolonged increase in blood glucose levels between 60 and 180 seconds.

Based on the insulin response and BGL measurements, a calibration ofcaloric intake may be performed for a patient. For example, knowncaloric intakes may be correlated with insulin response in phase 1 andphase 2 digestions measured using values for L_(390nm) 2902. In anotheraspect, the calibration table may be generated using testing of a sampleof a general population. It is determined that the R values usingL_(390nm) 2902 should correlate to similar caloric intake measurementsacross a general population. Thus, the calibration table may begenerated from testing of a sample of a general population.

Embodiment—Liver Enzyme Measurements

FIG. 30 illustrates a schematic drawing of an exemplary embodiment ofusing the biosensor 100 for measurements of a liver enzyme. Inunexpected results, concentration levels of a liver enzyme calledcytochrome P450 Oxidase (P450) 2900 was measured by the biosensor 100.In one aspect, spectral response around a wavelength at approximately468 nm was used by the biosensor 100 to obtain L values that tracked theconcentration levels of the liver enzyme P450 2900. The liver enzyme isgenerated to react with various substances 2902 and may be generated inresponse to alcohol levels. Thus, the measurement of the spectralresponse for the wavelength at approximately 468 nm may indicate bloodalcohol levels and/or concentration levels of P450 2900.

Embodiment—Measurements of other Substances

Using similar principles described herein, the biosensor 100 may measureconcentration levels or indicators of other substances in pulsatingblood flow. For example, using the process 1500 described with respectto FIG. 15, absorption coefficients for one or more frequencies thathave an intensity level responsive to concentration level of substancemay be determined. The biosensor 100 may then detect the substance atthe determined one or more frequencies as described herein and determinethe concentration levels using the Beer-Lambert principles and theabsorption coefficients. The L values and R values may be calculatedbased on the obtained spectral response. In one aspect, the biosensor100 may detect various electrolyte concentration levels or blood analytelevels, such as bilirubin and sodium and potassium. In another aspect,the biosensor 100 may detect sodium NACL concentration levels in thearterial blood flow to determine dehydration. In yet another aspect, thebiosensor 100 may be configured to detect proteins or abnormal cells orother elements or compounds associated with cancer. In another aspect,the PPG sensor may detect white blood cell counts.

FIG. 31 illustrates a schematic block diagram of an embodiment of amethod 3100 for determining concentration levels or indicators ofsubstances in pulsating blood flow in more detail. The biosensor 100obtains a spectral response signal at a first wavelength and at a secondwavelength at 3102. The spectral response signal includes AC and DCcomponents IAC+DC. A low pass filter is applied to the spectral responsesignal IAC+DC to isolate the DC component 3106 of the spectral responsesignal at each wavelength at 3104. The AC fluctuation is due to thepulsatile expansion of the arteriolar bed due to the volume increase inarterial blood. In order to measure the AC fluctuation, measurements aretaken at different times and a peak detection algorithm or other meansis used to determine the diastolic point and the systolic point of thespectral response at 3108. The systolic and diastolic measurements arecompared in order to compute the L values using Beer-Lambert equationsat 3110. For example, a logarithmic function may be applied to the ratioof I_(AC+DC) and I_(DC) to obtain an L value for the first wavelengthL_(λ1) and for the second wavelength L_(λ2). The ratio R of the firstwavelength L_(λ1) and for the second wavelength L_(λ2) may then becalculated at 3112. When multiple frequencies are used to determine aconcentration level of one or more substances, the the linear functiondescribed herein are applied at 3116, and the one or more concentrationlevels of the substances or analytes are determined at 3118.

In an embodiment, a substances or analyte may be attached in the bloodstream to one or more hemoglobin compounds. The concentration level ofthe hemoglobin compounds may then need to be subtracted from theconcentration level of the substance determined at 3118 to isolate theconcentration level of the substance at 3120 from the hemoglobincompounds. For example, nitric oxide (NO) is found in the blood streamin a gaseous form and also attached to hemoglobin compounds. Thus, themeasurements at L_(390nm) to detect nitric oxide may include aconcentration level of the hemoglobin compounds as well as nitric oxide.The hemoglobin compound concentration levels may then be determined andsubtracted to isolate the nitric oxide concentration levels. Thisprocess is discussed in more detail with respect to FIG. 32 below.

FIG. 32 illustrates a schematic block diagram of an exemplary embodimentof a graph 3200 illustrating the extinction coefficients over a range offrequencies for a plurality of hemoglobin compounds. The hemoglobincompounds include, e.g., Oxyhemoglobin [HbO2] 3202, Carboxyhemoglobin[HbCO] 3204, Methemoglobin [HbMet] 3206, and reduced hemoglobinfractions [RHb] 3208. As seen in FIG. 32, the biosensor 100 may controlthe PPG circuit 110 to detect the total concentration of the hemoglobincompounds using a center frequency of 660 nm and a range of 1 nm to 50nm. A method for determining the relative concentration or compositionof different kinds of hemoglobin contained in blood is described in moredetail in U.S. Pat. No. 6,104,938 issued on Aug. 15, 2000, which ishereby incorporated by reference herein.

Though the above description includes details with respect to pulsatingarterial blood flow, the biosensor 100 may use similar techniquesdescribed herein for pulsating venous blood flow. The biosensor 100 ispositioned on skin tissue over veins, such as on the wrist, and spectralresponses obtained from light reflected by or transmitted through thepulsating venous blood flow.

One or more embodiments have been described herein for the non-invasiveand continuous biosensor 100. Due to its compact form factor, thebiosensor 100 may be configured for measurements on various skinsurfaces of a patient, including on a forehead, arm, wrist, abdominalarea, chest, leg, ear lobe, finger, toe, ear canal, etc. The biosensorincludes one or more sensors for detecting biosensor data, such as apatient's vitals, activity levels, or concentrations of substances inthe blood flow of the patient. In particular, the PPG sensor isconfigured to monitor concentration levels or indicators of one or moresubstances in the blood flow of the patient. In one aspect, the PPGsensor may non-invasively and continuously detect diabetic parameters,such as insulin resistance, insulin response over time, nitric oxide(NO) levels, glucose levels, and predict diabetic risk or diabeticprecursors, in pulsatile arterial blood flow. In another aspect, the PPGsensor may measure vascular health using NO concentration levels. Inanother aspect, the PPG sensor may detect blood alcohol levels inpulsatile arterial blood flow. In another aspect, the PPG sensor maydetect cytochrome P450 proteins or one or more other liver enzymes orproteins. In another aspect, the PPG sensor may detect digestiveparameters, such as digestion phase 1 and 2 responses. The PPG sensormay detect various electrolyte concentration levels or blood analytelevels, such as bilirubin and sodium and potassium. For example, the PPGsensor may detect sodium NACL concentration levels in the arterial bloodflow to determine dehydration. In yet another aspect, the PPG sensor maybe configured to help diagnose cancer by detecting proteins or abnormalcells or other elements or compounds associated with cancer. In anotheraspect, the PPG sensor may detect white blood cell counts.

In one or more aspects herein, a processing module or circuit includesat least one processing device, such as a microprocessor,micro-controller, digital signal processor, microcomputer, centralprocessing unit, field programmable gate array, programmable logicdevice, state machine, logic circuitry, analog circuitry, digitalcircuitry, and/or any device that manipulates signals (analog and/ordigital) based on hard coding of the circuitry and/or operationalinstructions. A memory is a non-transitory memory device and may be aninternal memory or an external memory, and the memory may be a singlememory device or a plurality of memory devices. The memory may be aread-only memory, random access memory, volatile memory, non-volatilememory, static memory, dynamic memory, flash memory, cache memory,and/or any non-transitory memory device that stores digital information.

As may be used herein, the term “operable to” or “configurable to”indicates that an element includes one or more of circuits,instructions, modules, data, input(s), output(s), etc., to perform oneor more of the described or necessary corresponding functions and mayfurther include inferred coupling to one or more other items to performthe described or necessary corresponding functions. As may also be usedherein, the term(s) “coupled”, “coupled to”, “connected to” and/or“connecting” or “interconnecting” includes direct connection or linkbetween nodes/devices and/or indirect connection between nodes/devicesvia an intervening item (e.g., an item includes, but is not limited to,a component, an element, a circuit, a module, a node, device, networkelement, etc.). As may further be used herein, inferred connections(i.e., where one element is connected to another element by inference)includes direct and indirect connection between two items in the samemanner as “connected to”.

As may be used herein, the terms “substantially” and “approximately”provides an industry-accepted tolerance for its corresponding termand/or relativity between items. Such an industry-accepted toleranceranges from less than one percent to fifty percent and corresponds to,but is not limited to, frequencies, wavelengths, component values,integrated circuit process variations, temperature variations, rise andfall times, and/or thermal noise. Such relativity between items rangesfrom a difference of a few percent to magnitude differences.

Note that the aspects of the present disclosure may be described hereinas a process that is depicted as a schematic, a flowchart, a flowdiagram, a structure diagram, or a block diagram. Although a flowchartmay describe the operations as a sequential process, many of theoperations can be performed in parallel or concurrently. In addition,the order of the operations may be re-arranged. A process is terminatedwhen its operations are completed. A process may correspond to a method,a function, a procedure, a subroutine, a subprogram, etc. When a processcorresponds to a function, its termination corresponds to a return ofthe function to the calling function or the main function.

The various features of the disclosure described herein can beimplemented in different systems and devices without departing from thedisclosure. It should be noted that the foregoing aspects of thedisclosure are merely examples and are not to be construed as limitingthe disclosure. The description of the aspects of the present disclosureis intended to be illustrative, and not to limit the scope of theclaims. As such, the present teachings can be readily applied to othertypes of apparatuses and many alternatives, modifications, andvariations will be apparent to those skilled in the art.

In the foregoing specification, certain representative aspects of theinvention have been described with reference to specific examples.Various modifications and changes may be made, however, withoutdeparting from the scope of the present invention as set forth in theclaims. The specification and figures are illustrative, rather thanrestrictive, and modifications are intended to be included within thescope of the present invention. Accordingly, the scope of the inventionshould be determined by the claims and their legal equivalents ratherthan by merely the examples described. For example, the componentsand/or elements recited in any apparatus claims may be assembled orotherwise operationally configured in a variety of permutations and areaccordingly not limited to the specific configuration recited in theclaims.

Furthermore, certain benefits, other advantages and solutions toproblems have been described above with regard to particularembodiments; however, any benefit, advantage, solution to a problem, orany element that may cause any particular benefit, advantage, orsolution to occur or to become more pronounced are not to be construedas critical, required, or essential features or components of any or allthe claims.

As used herein, the terms “comprise,” “comprises,” “comprising,”“having,” “including,” “includes” or any variation thereof, are intendedto reference a nonexclusive inclusion, such that a process, method,article, composition or apparatus that comprises a list of elements doesnot include only those elements recited, but may also include otherelements not expressly listed or inherent to such process, method,article, composition, or apparatus. Other combinations and/ormodifications of the above-described structures, arrangements,applications, proportions, elements, materials, or components used inthe practice of the present invention, in addition to those notspecifically recited, may be varied or otherwise particularly adapted tospecific environments, manufacturing specifications, design parameters,or other operating requirements without departing from the generalprinciples of the same.

Moreover, reference to an element in the singular is not intended tomean “one and only one” unless specifically so stated, but rather “oneor more.” Unless specifically stated otherwise, the term “some” refersto one or more. All structural and functional equivalents to theelements of the various aspects described throughout this disclosurethat are known or later come to be known to those of ordinary skill inthe art are expressly incorporated herein by reference and are intendedto be encompassed by the claims. Moreover, nothing disclosed herein isintended to be dedicated to the public regardless of whether suchdisclosure is explicitly recited in the claims. No claim element isintended to be construed under the provisions of 35 U.S.C. §112(f) as a“means-plus-function” type element, unless the element is expresslyrecited using the phrase “means for” or, in the case of a method claim,the element is recited using the phrase “step for.”

1. A biosensor, comprising: a PPG circuit configured to: emit lighthaving at least a first wavelength and a second wavelength directed atskin tissue of a patient; generate a first spectral response using lightaround the first wavelength reflected from the skin tissue of thepatient; generate a second spectral response using light around thesecond wavelength reflected from the skin tissue of the patient; aprocessing circuit configured to: isolate a systolic point and adiastolic point in the first spectral response and obtain a value L_(λ1)using a ratio of the systolic point and the diastolic point in the firstspectral response; isolate a systolic point and a diastolic point in thesecond spectral response and obtain a value L_(λ2) using a ratio of thesystolic point and diastolic point in the second spectral response;obtain a value R_(λ1, λ2) from a ratio of the value L_(λ1) and the valueL_(λ2), wherein the value R_(λ1, λ2) is an indicator of one or moreliver enzymes; obtain a blood alcohol level using a calibration tableand the value R_(λ1, λ2); and transmit the blood alcohol level fordisplay.
 2. The biosensor of claim 1, wherein the first spectralresponse generated for light detected around the first wavelength isresponsive to a liver enzyme cytochrome oxidase (P450) released inresponse to alcohol in pulsating arterial blood flow.
 3. The biosensorof claim 2, wherein the value R_(λ1, λ2) obtained from the ratio of thevalue L_(λ1) and the value L_(λ2) correlates to an indicator of the P450liver enzyme.
 4. The biosensor of claim 3, wherein the processingcircuit is further configured to output the indicator of the P450 liverenzyme.
 5. The biosensor of claim 4, wherein the first frequency has ahigh absorption coefficient for the P450 liver enzyme.
 6. The biosensorof claim 5, wherein the first frequency is at approximately 468 nm. 7.The biosensor of claim 5, wherein the second frequency has a lowabsorption coefficient for the P450 liver enzyme.
 8. The biosensor ofclaim 5, wherein the PPG circuit is configured to generate the firstspectral response for light detected at the wavelength of 468 nm and forwavelengths in a range of 1 nm to 50 nm around 468 nm.
 9. The biosensorof claim 8, wherein the calibration table includes a range of R_(λ1, λ2)values and correlated blood alcohol levels, wherein the calibrationtable is generated using blood alcohol level measurements obtained froma sample population during a same measurement period as the range ofR_(λ1, λ2) values is obtained by the biosensor for the samplepopulation.
 10. A biosensor, comprising: a PPG circuit configured to:generate at least a first spectral response for light reflected around afirst wavelength from skin tissue of the patient; generate at least asecond spectral response for light reflected around a second wavelengthfrom the skin tissue of the patient; a processing circuit configured to:obtain a value L_(λ1) using the first spectral response, wherein thevalue L_(λ1) isolates the first spectral response due to pulsatingarterial blood flow; obtain a value L_(λ2) using the second spectralresponse, wherein the value L_(λ2) isolates the second spectral responsedue to pulsating arterial blood flow; obtain a value R_(λ1, λ2) from aratio of the value L_(λ1) and the value L_(λ2); obtain a liver enzymeindicator based on the value R_(λ1, λ2) that indicates a liver enzymeconcentration level in the pulsating arterial blood flow; and obtain ablood alcohol level using a calibration table and the value R_(λ1, λ2).11. The biosensor of claim 10, further comprising: a wirelesstransceiver configured to transmit the blood alcohol level to a remotedevice.
 12. The biosensor of claim 10, wherein the first spectralresponse generated for light detected around the first wavelength isresponsive to a liver enzyme, wherein a concentration level of the liverenzyme increases in the pulsating arterial blood flow in response toalcohol intake by the patient.
 13. The biosensor of claim 12, whereinthe liver enzyme includes cytochrome oxidase (P450). The biosensor ofclaim 13, wherein the first frequency has a high absorption coefficientfor P450 and the second frequency has a low absorption coefficient forP450.
 15. The biosensor of claim 14, wherein the first frequency isapproximately 468 nm and the second frequency is approximately 940 nm.16. The biosensor of claim 13, wherein the PPG circuit is configured togenerate the first spectral response for light detected at thewavelength of 468 nm and for wavelengths in a range of 1 nm to 50 nmaround 468 nm.
 17. The biosensor of claim 16, wherein the calibrationtable includes a range of R_(λ1, λ2) values and correlated blood alcohollevels, wherein the calibration table is generated using blood alcohollevel measurements obtained from a sample population during a samemeasurement period as the range of R_(λ1, λ2) values is obtained by thebiosensor of the sample population.
 18. A method for measuring bloodalcohol levels, comprising: generating at least a first spectralresponse for light reflected around a first wavelength from skin tissueof the patient; generating at least a second spectral response for lightdetected around a second wavelength reflected from the skin tissue ofthe patient; obtaining a value L_(λ1) using the first spectral response,wherein the value L_(λ1) isolates the first spectral response due topulsating arterial blood flow; obtaining a value L_(λ2) using the secondspectral response, wherein the value L_(λ2) isolates the second spectralresponse due to pulsating arterial blood flow; obtaining a valueR_(λ1, λ2) from a ratio of the value L_(λ1) and the value L_(λ2),wherein the value R_(λ1, λ2) is the indicator of a concentration levelof a liver enzyme of the patient; obtaining a blood alcoholconcentration level of the patient from a calibration table and thevalue R_(λ1, λ2), wherein the calibration table includes a range ofR_(λ1, λ2) values and correlated blood alcohol concentration levels; andtransmitting the blood alcohol concentration level of the patient fordisplay.
 19. The method of claim 18, wherein the first spectral responsefor light reflected around a first wavelength from skin tissue of thepatient is responsive to a liver enzyme cytochrome oxidase (P450)released in response to alcohol in pulsating arterial blood flow. 20.The biosensor of claim 19, wherein the calibration table includes arange of R_(λ1, λ2) values and correlated blood alcohol levels, whereinthe calibration table is generated using blood alcohol levelmeasurements obtained from a sample population during a same measurementperiod as the range of R_(λ1, λ2) values is obtained by the biosensor ofthe sample population.
 21. A biosensor configured for installation inmachinery, comprising: a PPG circuit configured to: generate at least afirst spectral response for light reflected around a first wavelengthfrom skin tissue of the patient; generate at least a second spectralresponse for light reflected around a second wavelength from the skintissue of the patient; a processing circuit configured to: obtain avalue L_(λ1) using the first spectral response, wherein the value L_(λ1)isolates the first spectral response due to pulsating arterial bloodflow; obtain a value L_(λ2) using the second spectral response, whereinthe value L_(λ2) isolates the second spectral response due to pulsatingarterial blood flow; obtain a value R_(λ1, λ2) from a ratio of the valueL_(λ1) and the value L_(λ2); obtain a liver enzyme indicator based onthe value R_(λ1, λ2) that indicates a liver enzyme concentration levelin the pulsating arterial blood flow; obtain a blood alcohol level usinga calibration table and the value R_(λ1, λ2); and generate atransmission to the machinery to control operation of the machinery inresponse to the blood alcohol level.
 22. The biosensor of claim 21,wherein the processing circuit is further configured to: compare theblood alcohol level to a predetermined threshold; determine the bloodalcohol level exceeds the predetermined threshold; and generate atransmission to an ignition system of the vehicle to prevent operationof the machinery.